Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women with bipolar disorder

Biol Psychiatry. 2006 Jun 1;59(11):1078-86. doi: 10.1016/j.biopsych.2005.10.017. Epub 2006 Jan 31.


Background: Preliminary evidence suggests that valproate is associated with isolated features of polycystic ovarian syndrome (PCOS), while contradictory data support an association between epilepsy and PCOS. The development of PCOS features after initiation of valproate was therefore examined in women with bipolar disorder using a standardized definition of PCOS.

Methods: Three hundred women 18 to 45 years old with bipolar disorder were evaluated for PCOS at 16 Systematic Treatment Enhancement for Bipolar Disorder sites. A comparison was made between the incidence of hyperandrogenism (hirsutism, acne, male-pattern alopecia, elevated androgens) with oligoamenorrhea that developed while taking valproate versus other anticonvulsants (lamotrigine, topiramate, gabapentin, carbamazepine, oxcarbazepine) and lithium. Medication and menstrual cycle histories were obtained, and hyperandrogenism was assessed.

Results: Among 230 women who could be evaluated, oligoamenorrhea with hyperandrogenism developed in 9 (10.5%) of 86 women on valproate and in 2 (1.4%) of 144 women on a nonvalproate anticonvulsant or lithium (relative risk 7.5, 95% confidence interval [CI] 1.7-34.1, p = .002). Oligoamenorrhea always began within 12 months of valproate use.

Conclusions: Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism. Monitoring for reproductive-endocrine abnormalities is important when starting and using valproate in reproductive-aged women. Prospective studies are needed to elucidate risk factors for development of PCOS on valproate.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amenorrhea / chemically induced*
  • Amenorrhea / epidemiology
  • Antimanic Agents / adverse effects*
  • Bipolar Disorder / drug therapy*
  • Cohort Studies
  • Comorbidity
  • Female
  • Humans
  • Hyperandrogenism / chemically induced*
  • Hyperandrogenism / epidemiology
  • Incidence
  • Longitudinal Studies
  • Middle Aged
  • Oligomenorrhea / chemically induced*
  • Oligomenorrhea / epidemiology
  • Risk Factors
  • Time Factors
  • Valproic Acid / adverse effects*


  • Antimanic Agents
  • Valproic Acid