Evaluation of reproductive function in women treated for bipolar disorder compared to healthy controls.

The reproductive function of women with bipolar disorder (BD) is of increasing interest to clinicians and patients alike. Previous studies have suggested that some medications used to treat BD, particularly anti-epileptic drugs (AEDs) such as valproate (VPA), are associated with a higher incidence of menstrual abnormalities (MA) and polycystic ovary syndrome (PCOS) (1–6), a poorly understood endocrine disorder characterized by chronic anovulation and hyperandrogenism (7). However, there has been some disagreement in the literature regarding this association (8–12). In women with epilepsy treated with AEDs, it has been proposed that reproductive dysfunction may be influenced by both medications and the neuroendocrine effects of epilepsy itself (13, 14). A similar question has been raised in the population of women with BD, given that the neuroendocrine systems are central to both reproductive function and mood disorders (15). In addition, individuals with BD are often treated with combinations of psychotropic medications including atypical antipsychotics (AAPs), a class of medication that has been associated with weight gain, central adiposity, and the development of insulin resistance and type 2 diabetes (16–18). PCOS is one of the most common endocrine disorders in women, with an estimated incidence between 4% and 6% (19–21). In addition to being one of the most common causes of anovulatory infertility, PCOS is associated with an increased risk for type 2 diabetes, impaired glucose utilization, and cardiovascular disease (22–24). The standardized definition of PCOS has evolved over time and has varied in literature before the development of the standardized Rotterdam criteria (last revised in 2003), which proposed that PCOS be diagnosed based on fulfilling two of the following three criteria: oligomenorrhea or amenorrhea, clinical and/or biochemical hyperandrogenism, and polycystic ovaries (25). This has led to some disagreement as it has been argued that these criteria are not robust enough to support discerning clinical research (26–29). For example, the Androgen Excess Society regards hyperandrogenism as necessary for a diagnosis, along with either anovulation or polycystic ovary morphology (30). We have previously reported high rates of MAs in women with BD, around 40% of whom report a current or previous MA (31–33), similar to rates published by others (5, 34). We have also reported cases of MA associated with VPA use in a cross-sectional study design (31), with length of VPA exposure being significantly associated with free testosterone levels and VPA use being associated with an increase over time in total testosterone in a longitudinal study setting (32). However, no studies to our knowledge have been able to compare these rates to a control population. Similarly, no studies have integrated an objective, longitudinal determination of ovulation simultaneously with self-report measures of menstrual cycle length. This study aimed to bring together cross-sectional biochemical assessments, self-report questionnaire data regarding reproductive functioning, and longitudinal, prospective ovulation tracking in women with BD and compare these measures of reproductive function to a control group of healthy women with no psychiatric history.