Reduction in hematocrit level after pioglitazone treatment is correlated with decreased plasma free testosterone level, not hemodilution, in women with polycystic ovary syndrome
Reduction in hematocrit level after pioglitazone treatment is correlated with decreased plasma free testosterone level, not hemodilution, in women with polycystic ovary syndrome
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DOI：
10.1016/j.clpt.2006.03.014
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发表时间：
2006-08-01
影响因子：
6.7
通讯作者：
DeFronzo, Ralph
中科院分区：
文献类型：
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作者：
Berria, Rachele;Gastaldelli, Amalia;DeFronzo, Ralph
噻唑烷二酮类药物已广泛用于治疗2型糖尿病和其他胰岛素抵抗状态，包括多囊卵巢综合征（PCOS）。在噻唑烷二酮治疗的患者中，经常观察到血红蛋白和红细胞压积水平的小幅度下降，这通常归因于液体潴留。由于睾酮是一种造血激素，我们研究了22名接受吡格列酮45mg /d治疗的PCOS患者（9名糖耐量正常，13名糖耐量受损，平均年龄29.5岁，平均体重指数35.6 +/- 5.8 kg/m(2)）血浆游离睾酮浓度的降低是否与血红蛋白和红细胞压容水平的降低有关。治疗前和4个月后，受试者进行口服葡萄糖耐量试验和生物阻抗法测定全身含水量。血浆睾酮、雄烯二酮、硫酸脱氢表雄酮、血红蛋白和血细胞比容水平在基线和每个月进行评估，持续4个月。吡格列酮治疗后空腹血糖浓度（98.9 mg/dL）没有变化，而2小时血糖浓度从144.6 mg/dL下降到119.20 mg/dL （P = 0.002）。根据Vermeulen等计算的游离雄激素指数和游离睾酮水平均显著下降（分别从14.4 +/- 7.1降至10.6 +/- 7.8 [P = .02]和59.4 +/- 23.4降至46.6 +/- 23.3 [P = = .03]）。血浆雄烯二酮水平从259 +/- 134降至190 +/- 109 ng/dL (P = 0.01)，而硫酸脱氢表雄酮水平变化不显著（从13990降至127 +/- 84 μ g/dL， P = 0.2[无统计学意义]）。使用吡格他酮4个月后，血红蛋白（从13.6 +/- 1.0降至12.8 +/- 1.1 g/dL, P = .0002）和红细胞压容（从39.7% +/- 2.2%降至37.9% +/- 2.7%,P = .002）均略有下降。Vermeulen等计算的吡格列酮给药前后血浆游离睾酮水平与血红蛋白（r = 0.49, P < 0.0001）、红细胞压积（r = 0.40, P < 0.0001）、游离雄激素指数（r = 0.38 [P < .0003]与血红蛋白、r = 0.29 [P < .006]）呈正相关；血浆游离睾酮水平和游离雄激素指数的下降也与血红蛋白（r = 0.51 [P = 0.01]和r = 0.54 [P = 0.01]）和红细胞压积（r = 0.42 [P = 0.05]和r = 0.50 [P = 0.02]）的下降相关。服用吡格列酮后，体重从90.5 +/- 17.3 kg增加到92.4 +/- 18.8 kg (P = 0.05)，体脂含量也从42.7 +/- 15.3 kg增加到44.8 +/- 17.1 kg, P = 0.03)，这可以解释体重增加的原因，因为所有受试者均未出现水肿。服用吡格列酮后，小鼠体内总含水量无显著变化（从37.7 +/- 5.0 L降至37.8 +/- 4.9 L, P = 0.68[无统计学意义]）。综上所述，吡格列酮治疗与红细胞压积或血红蛋白水平轻度下降相关，这与血浆睾酮水平降低相关。这些结果表明，体内水分含量的增加不能解释多囊卵巢综合征女性红细胞压积或血红蛋白水平的降低。需要进一步的研究来评估同样的情况是否适用于正常雄激素分泌的女性和2型糖尿病患者。
Thiazolidinediones have gained widespread use for the treatment of type 2 diabetes mellitus and other insulin resistance states, including polycystic ovary syndrome (PCOS). In thiazolidinedione-treated patients a small reduction in hemoglobin and hematocrit levels often is observed, and this generally has been attributed to fluid retention. Because testosterone is a hematopoictic hormone, we investigated whether a reduction in plasma free testosterone concentration was associated with the decrease in hemoglobin and hematocrit levels in 22 nondiabetic women (9 with normal glucose tolerance and 13 with impaired glucose tolerance; mean age, 29 :L 5 years; mean body mass index, 35.6 +/- 5.8 kg/m(2)) with PCOS who were treated with pioglitazone, 45 mg/d. Before treatment and after 4 months, subjects underwent an oral glucose tolerance test and measurement of total body water content with bioimpedance. Plasma testosterone, androstenedione, dehydroepiandrosterone sulfate, hemoglobin, and hematocrit levels were evaluated at baseline and every month for 4 months. The fasting plasma glucose concentration (98 9 mg/dL) was unchanged after pioglitazone treatment, whereas the 2-hour plasma glucose concentration declined from 146 41 to 119 20 mg/dL (P = .002). Both the free androgen index and the free testosterone levels calculated according to Vermeulen et al decreased significantly (from 14.4 +/- 7.1 to 10.6 +/- 7.8 [P = .02] and from 59.4 +/- 23.4 to 46.6 +/- 23.3 [P = = .03], respectively). The plasma androstenedione level declined from 259 +/- 134 to 190 +/- 109 ng/dL (P = .01), whereas the dehydroepiandrosterone sulfate level did not change significantly (from 139 90 to 127 +/- 84 mu g/dL, P = .2 [not significant]). The levels of both hemoglobin (from 13.6 +/- 1.0 to 12.8 +/- 1.1 g/dL, P = .0002) and hematocrit (from 39.7% +/- 2.2% to 37.9% +/- 2.7%, P = .002) fell slightly after 4 months of pioghtazone administration. Collectively, before and after pioglitazone administration, the plasma free testosterone level according to Vermeulen et al correlated positively with the levels of hemoglobin (r = 0.49, P < .0001) and hematocrit (r = 0.40, P < .0001), as well as the free androgen index (r = 0.38 [P < .0003] with hemoglobin and r = 0.29 [P < .006] with hematocrit); the decrement in plasma free testosterone level and free androgen index also correlated with the decrements in the levels of both hemoglobin (r = 0.51 [P = .01] and r = 0.54 [P = .01], respectively) and hematocrit (r 0.42 [P =.05] and r = 0.50 [P = .02], respectively). Body weight increased from 90.5 +/- 17.3 to 92.4 +/- 18.8 kg after pioglitazone administration (P = .05), as did body fat content (from 42.7 +/- 15.3 to 44.8 +/- 17.1 kg, P = .03), which could explain the increase in weight, because edema did not develop in any of the subjects. Total body water content did not change significantly after pioglitazone administration (from 37.7 +/- 5.0 to 37.8 +/- 4.9 L, P = .68 [not significant]). In summary, pioglitazone treatment is associated with a mild decline in hernatocrit or hemoglobin level, which is correlated with the reduction in plasma testosterone level. These results suggest that increased body water content cannot explain the reduction in hematocrit or hemoglobin level in women with PCOS. Further studies are necessary to evaluate whether the same scenario is applicable to normoandrogenic women and individuals with type 2 diabetes mellitus.