Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome
Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome
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DOI：
10.1210/jc.85.8.2767
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发表时间：
2000-08-01
影响因子：
5.8
通讯作者：
Morselli-Labate, AM
中科院分区：
文献类型：
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作者：
Pasquali, R;Gambineri, A;Morselli-Labate, AM
腹型肥胖和高胰岛素血症在多囊卵巢综合征（PCOS）的发生发展中起着关键作用。饮食诱导的体重减轻和使用降胰岛素药物（如二甲双胍）通常会改善高雄激素血症和相关的临床异常。本研究旨在评估低热量饮食和二甲双胍联合治疗对20名肥胖PCOS女性[体重指数（BMI）> 28 kg/m2]腹部表型的体重、脂肪分布、葡萄糖-胰岛素系统和激素的影响。（腰臀比>0.80），以及20名年龄和体脂分布模式相当但无PCOS的肥胖妇女的适当对照组。在基线时，我们测量性激素、性激素结合球蛋白（SHBG）和瘦素的血液浓度，并进行口服葡萄糖耐量试验和L4-L5水平的计算机断层扫描（CT），以测量皮下脂肪组织面积（SAT）和内脏脂肪组织面积。所有女性随后仅给予低热量饮食（1200-1400千卡/天）一个月，之后重新测量人体测量参数和CT扫描。在继续饮食治疗的同时，PCOS女性和肥胖对照随后按照随机顺序，根据双盲设计，接受二甲双胍（850 mg/os，每日两次）（分别为12和8）或安慰剂（分别为8和12），持续6个月。在研究结束时，每名妇女在仍在接受治疗时进行血液检查和CT扫描。在治疗期间，对照组的3名妇女（均接受安慰剂治疗）因不依从而被排除; 2名PCOS妇女（均接受二甲双胍治疗）也因怀孕而被排除。因此，可用于最终统计分析的女性队列包括18名PCOS患者（10名接受二甲双胍治疗，8名接受安慰剂治疗）和17名对照女性（8名接受二甲双胍治疗，9名接受安慰剂治疗）。在PCOS组中，二甲双胍治疗改善多毛和月经周期的效果显著优于安慰剂。所有组的基线人体测量和CT参数相似。在PCOS组和对照组中，低热量饮食1个月同样降低了BMI值和腰围，对CT扫描参数没有任何显著影响。然而，在PCOS和对照组妇女中，二甲双胍治疗降低体重和BMI的效果显著优于安慰剂。无论药物治疗如何，PCOS妇女和对照组的腰臀比变化相似。二甲双胍治疗显著降低了PCOS组和对照组的SAT值，尽管仅在后一组中SAT的变化显著大于安慰剂治疗期间观察到的变化。相反，二甲双胍治疗期间，PCOS和对照组的内脏脂肪组织面积值均显著降低，但仅在前者中二甲双胍治疗的效果显著高于安慰剂。无论治疗如何，PCOS妇女和对照组的空腹胰岛素均显著降低，而葡萄糖刺激的胰岛素仅在接受二甲双胍治疗的PCOS妇女和对照组中显著降低。二甲双胍或安慰剂均未显著改变任何组的LH、FSH、硫酸脱氢表雄酮和孕酮水平，而睾酮浓度仅在二甲双胍治疗的PCOS女性中降低。所有PCOS女性的SHBG浓度保持不变;而在对照组中，二甲双胍和安慰剂后SHBG浓度显著增加。总之，本研究表明，在PCOS腹部肥胖的妇女，长期二甲双胍治疗加低热量饮食诱导，与安慰剂相比，体重和腹部脂肪，特别是内脏贮库，更大的减少和更一致的血清胰岛素，睾酮和瘦素浓度降低。这些变化与多毛症和月经异常的更显着改善有关。此外，对体重、胰岛素和瘦素的影响与腹部肥胖对照组相似，但腹部脂肪减少更明显，SHBG浓度增加，因此，这些发现表明，高胰岛素血症和腹部肥胖在PCOS的发病机制中可能具有互补作用。
Abdominal obesity and hyperinsulinemia play a key role in the development of the polycystic ovary syndrome (PCOS). Dietary-induced weight loss and the administration of insulin-lowering drugs, such as metformin, are usually followed by improved hyperandrogenism and related clinical abnormalities. This study was carried out to evaluate the effects of combined hypocaloric diet and metformin on body weight, fat distribution, the glucose-insulin system, and hormones in a group of 20 obese PCOS women [body mass index (BMI) > 28 kg/m(2)] with the abdominal phenotype (waist to hip ratio >0.80), and an appropriate control group of 20 obese women who were comparable for age and pattern of body fat distribution but without PCOS. At baseline, we measured sex hormone, sex hormone-binding globulin (SHBG), and leptin blood concentrations and performed an oral glucose tolerance test and computerized tomography (CT) at the L4-L5 level, to measure sc adipose tissue area (SAT) and visceral adipose tissue area. All women were then given a low-calorie diet (1200-1400 kcal/day) alone for one month, after which anthropometric parameters and CT scan were newly measured. While continuing dietary treatment, PCOS women and obese controls were subsequently placed, in a random order, on metformin (850 mg/os, twice daily) (12 and 8, respectively) or placebo (8 and 12, respectively), according to a double-blind design, for the following 6 months. Blood tests and the CT scan were pel formed in each woman at the end of the study while they were still on treatment.During the treatment period, 3 women of the control group (all treated with placebo) were excluded because of noncompliance; and 2 PCOS women, both treated with metformin, were also excluded because they became pregnant. Therefore, the women cohort available for final statistical analysis included 18 PCOS (10 treated with metformin and 8 with placebo) and 17 control women (8 treated with metformin and 9 with placebo).The treatment was well tolerated. In the PCOS group, metformin therapy improved hirsutism and menstrual cycles significantly more than placebo. Baseline anthropometric and CT parameters were similar in all groups. Hypocaloric dieting for 1 month similarly reduced BMI values and the waist circumference in both PCOS and control groups, without any significant effect on CT scan parameters. In both PCOS and control women, however, metformin treatment reduced body weight and BMI significantly more than placebo. Changes in the waist-to-hip ratio values were similar in PCOS women and controls, regardless of pharmacological treatment. Metformin treatment significantly decreased SAT values in both PCOS and control groups, although only in the latter group were SAT changes significantly greater than those observed during the placebo treatment. On the contrary, visceral adipose tissue area values significantly decreased during metformin treatment in both PCOS and control groups, but only in the former was the effect of metformin treatment significantly higher than that of placebo.Fasting insulin significantly decreased in both PCOS women and controls, regardless of treatment, whereas glucose-stimulated insulin significantly decreased only in PCOS women and controls treated with metformin. Neither metformin or placebo significantly modified the levels of LH, FSH, dehydroepiandrosterone sulphate, and progesterone in any group, whereas testosterone concentrations decreased only in PCOS women treated with metformin. SHBG concentrations remained unchanged in all PCOS women; whereas in the control group, they significantly increased after both metformin and placebo. Leptin levels decreased only during metformin treatment in both PCOS and control groups.In summary, this study shows that, in PCOS women with abdominal obesity, long-term treatment with metformin added to hypocaloric diet induced, in comparison with placebo, a greater reduction of body weight and abdominal fat, particularly the visceral depots, and a more consistent decrease of serum insulin, testosterone, and leptin concentrations. These changes were associated with a more significant improvement of hirsutism and menses abnormalities. Moreover, the effects on body weight, insulin, and leptin were similar to those observed in the group of comparable abdominally obese controls, in whom, however, a more pronounced reduction of se fat in the abdominal region and an increase of SHBG concentrations were found. These findings, therefore, indicate that hyperinsulinemia and abdominal obesity may have complementary effects in the pathogenesis of PCOS.