Departments of Pharmaceutics (W.Z., T.H., J.W.), Pharmacy (M.F.H.), and Obstetrics and Gynecology (M.F.H.), University of Washington, Seattle, Washington.
Departments of Pharmaceutics (W.Z., T.H., J.W.), Pharmacy (M.F.H.), and Obstetrics and Gynecology (M.F.H.), University of Washington, Seattle, Washington
J Pharmacol Exp Ther. 2019 Oct;371(1):113-120. doi: 10.1124/jpet.118.255380. Epub 2019 Jul 15.
Long-term use of selective serotonin reuptake inhibitors (SSRIs) targeting the serotonin transporter (SERT) has been suggested to be associated with an increased risk for obesity and type 2 diabetes. Previously, using a murine knockout model of SERT, we showed that estrogen suppression is involved in SERT deficiency-induced obesity and glucose intolerance in nonpregnant mice. The present study investigated the effects of chronic paroxetine treatment on adiposity and glucose tolerance in mice before and during pregnancy. Chronic paroxetine treatment in nonpregnant mice resulted in visceral adiposity and glucose intolerance accompanied by reduced circulating 17-estradiol levels and ovarian expression of the aromatase (CYP19a1). Remarkably, pregnancy significantly reduced adiposity and improved glucose tolerance in paroxetine-treated mice by rebooting ovarian CYP19a1 expression and 17-estradiol production. These effects appear to be reversible as ovarian CYP19a1 expression and circulating 17-estradiol returned to prepregnancy levels soon after parturition. As in pregnant mice, 17-estradiol replacement treatment in nonpregnant mice reduced paroxetine-induced adiposity. Our findings further suggested that modulation of estrogen synthesis underlies the observed metabolic adverse effects of SSRIs. Although our data revealed a transient reversal effect of pregnancy on SSRI-induced metabolic abnormalities, these observations are experimental and limited to mice. The use of SSRIs during human pregnancy should be cautioned because of potential adverse effects to the fetuses.
长期使用选择性 5-羟色胺再摄取抑制剂（SSRIs）靶向 5-羟色胺转运体（SERT）已被认为与肥胖和 2 型糖尿病的风险增加有关。先前，我们使用 SERT 敲除的小鼠模型表明，雌激素抑制参与了 SERT 缺乏诱导的非妊娠小鼠肥胖和葡萄糖耐量受损。本研究在妊娠前和妊娠期间调查了慢性帕罗西汀治疗对小鼠肥胖和葡萄糖耐量的影响。非妊娠小鼠的慢性帕罗西汀治疗导致内脏肥胖和葡萄糖耐量受损，同时伴有循环 17-雌二醇水平降低和卵巢芳香酶（CYP19a1）表达减少。值得注意的是，妊娠通过重新启动卵巢 CYP19a1 表达和 17-雌二醇的产生，显著降低了帕罗西汀治疗小鼠的肥胖程度并改善了葡萄糖耐量。这些作用似乎是可逆的，因为卵巢 CYP19a1 表达和循环 17-雌二醇在分娩后不久恢复到妊娠前水平。与妊娠小鼠一样，非妊娠小鼠的 17-雌二醇替代治疗降低了帕罗西汀引起的肥胖。我们的研究结果进一步表明，雌激素合成的调节是 SSRIs 引起的代谢不良反应的基础。尽管我们的数据揭示了妊娠对 SSRI 诱导的代谢异常的短暂逆转效应，但这些观察结果是实验性的，仅限于小鼠。由于对胎儿的潜在不良影响，应谨慎在人类妊娠期间使用 SSRIs。
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