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Endocrine and Metabolic Responses to Long-Term Monotherapy with the Antiepileptic Drug Valproate in the Normally Cycling Rhesus Monkey

Departments of Obstetrics and Gynecology, and Neurology (M.F., M.M., E.X., F.Q., T.W., M.S.), Columbia University College of Physicians and Surgeons, New York, New York 10032; and Abbott Laboratories (L.K.), Abbott Park, Illinois 60064

Address all correspondence and requests for reprints to: Dr. Michel Ferin, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: mf8{at}columbia.edu.

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) µg/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 GnRH agonist 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.

This work was supported in part by a grant from Abbott Laboratories.

Abbreviations: CV, Coefficient(s) of variation; DCL, degenerating corpora lutea; DHEAS, dehydroepiandrosterone sulfate; NS, not significant; PCOS, polycystic ovarian syndrome; RCL, recent corpora lutea; VPA, valproate.

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