Endocrine and metabolic responses to long-term monotherapy with the antiepileptic drug valproate in the normally cycling rhesus monkey
Endocrine and metabolic responses to long-term monotherapy with the antiepileptic drug valproate in the normally cycling rhesus monkey
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DOI：
10.1210/jc.2002-021614
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发表时间：
2003-06-01
影响因子：
5.8
通讯作者：
Sauer, M
中科院分区：
文献类型：
--
作者：
Ferin, M;Morrell, M;Sauer, M
多囊卵巢综合征(PCOS)的发病率明显增加，癫痫与生殖障碍之间的关系已有报道。这种联系是否可以归因于癫痫本身，或者与抗癫痫药物治疗，特别是丙戊酸盐(VPA)有关，仍然存在争议。我们研究了长期VPA治疗对骑行猴子的影响，假设如果VPA单一治疗促进多囊卵巢综合征特征的异常内分泌和代谢参数，将很容易显示出周期性的变化。经过2个月的对照，7只定期骑行的恒河猴开始了为期12至15个月的VPA单一治疗。VPA的总体平均水平为88.7+/-4.0(SE)µg/ml。在VPA治疗期间，平均体重从治疗前的8.5+/-0.5公斤递增到治疗最后一周的9.6+/-0.7公斤(P<；0.05)。在VPA单一治疗期间，猴子继续有规律的排卵月经周期。对照组为28±0.58d，VPA治疗后3个月为28.4±1.18d。对照组和治疗组的卵泡和黄体长度以及排卵前雌二醇和黄体孕酮的峰值水平没有差异。VPA处理的猴子的卵巢显示出排卵的组织学证据，但没有一只具有PCOS的特征。在对照组和VPA治疗周期中，内分泌PCOS指标，如早期卵泡黄体生成素/卵泡刺激素比值和雄激素水平的增加没有差别。对照组和VPA组的促黄体生成素和17-羟孕酮对GnRH激动剂挑战的反应以及对糖耐量试验的胰岛素反应相似。VPA治疗对血脂谱无影响。这些数据表明，当给非癫痫的正常周期的非人类灵长类动物服用VPA 12至15个月的治疗性暴露时，不会引起周期激素或卵巢形态的异常或PCOS的特征。
An association between epilepsy and reproductive disturbances with an apparent increase in a polycystic ovarian syndrome ( PCOS) has been reported. Whether this association can be attributed to epilepsy itself or is related to antiepileptic drug therapy, in particular valproate ( VPA), remains controversial. We studied effects of a long- term VPA treatment on cycling monkeys, postulating that, if VPA monotherapy were to promote abnormal endocrine and metabolic parameters that are characteristic of PCOS, changes in cyclicity would be readily demonstrated.After a 2- month control, a 12- to 15- month VPA monotherapy was initiated in 7 regularly cycling rhesus monkeys. Overall mean levels of VPA were 88.7 +/- 4.0 ( SE) mu g/ ml. Mean body weight increased progressively during VPA treatment from 8.5 +/- 0.5 kg before treatment to 9.6 +/- 0.7 kg in the last week of treatment ( P < 0.05). Monkeys continued to have regular ovulatory menstrual cycles throughout VPA monotherapy. Length of the cycles was 28 +/- 0.58 d in control and 28.4 +/- 1.18 d in the last 3 months of VPA treatment. Follicular and luteal lengths and peak preovulatory estradiol and integrated luteal progesterone levels did not differ between control and treatment. Ovaries from VPA- treated monkeys showed histological evidence of ovulation, and none had characteristic features of PCOS. Endocrine PCOS markers, such as increased early follicular LH/ FSH ratio and androgen levels were not different in control and VPA treatment cycles. LH and 17- hydroxyprogesterone responses to GnRHagonist challenges and the insulin response to glucose tolerance tests were similar in control and VPA groups. Lipid profiles were not affected by VPA treatment. The data indicate that a 12- to 15- month therapeutic exposure to VPA does not induce cyclic hormonal or morphological ovarian abnormalities or characteristics of the PCOS when administered to nonepileptic normally cycling nonhuman primates.