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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age (Franks, 1995). It is defined as an increase of serum testosterone levels (hyperandrogenism) and chronic anovulation in the absence of specific underlying diseases of the adrenal or pituitary glands (Zawadski and Dunaif, as cited in Franks, 1995).
Cardinal clinical characteristics of PCOS are hirsutism, acne and alopecia. Anovulation may manifest clinically as amenorrhea or irregular menses and may ultimately result in infertility. Other endocrine abnormalities have been associated with PCOS, such as fasting and glucose-stimulated hyperinsulemia, peripheral insulin resistance, and chronically elevated plasma free estrogen and testosterone levels (Franks, 1995; Yen, as cited in Rasgon et al., 2000). In addition, approximately 50% of women with PCOS are obese (Pasquali and Casimirri, 1993), which may contribute to insulin resistance and other symptoms of PCOS. Figure 1 depicts a possible model for the pathophysiology of PCOS.
The fundamental defect in PCOS is unclear, but theories implicate dysfunction of the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes and related neurochemical systems. Insulin resistance may be a critical pathogenic mechanism, which is supported by the finding that women with PCOS show greater prevalence of glucose intolerance and frank type 2 diabetes mellitus (Pierpoint et al., 1998).
Regardless of treatment, women with epilepsy demonstrate an increased prevalence of PCOS compared to healthy women (Herzog et al., 1984). This relationship can be further complicated by drug therapy, as anticonvulsants (valproate [Depakene], carbamazepine [Tegretol] and lithium) often used to treat epilepsy may change the serum concentrations of sex hormones. Anticonvulsants have been reported to change the metabolism of reproductive hormones resulting in alteration of circulating blood levels of these hormones and secondary effects on the feedback loop of the HPG axis (Mattson and Cramer, 1985).
In 1993, Isojrvi et al. reported increased menstrual disturbances, polycystic ovaries and hyperandrogenism in women with epilepsy treated with valproate, compared to healthy women or women with epilepsy treated with carbamazepine alone or other medications not including valproate. Forty-three percent of the women receiving valproate had polycystic ovaries, confirmed by ultrasound, and 17% had elevated serum testosterone concentrations without polycystic ovaries. Moreover, the majority of women treated with valproate before the age of 20 had polycystic ovaries or hyperandrogenism.
A more recent report investigated the role of obesity in the relationship between endocrine disorders and women taking valproate for epilepsy (Isojrvi et al., 1996). Treatment of epilepsy with valproate has been associated with weight gain in approximately 50% of female patients (Dinesen et al., 1984; Egger and Brett, 1981). Isojrvi et al. (1996) found this weight gain to be related to hyperinsulinemia and low serum levels of insulin-like growth factor-binding protein 1, which may lead to hyperandrogenism and PCOS.
Further, Isojrvi et al. (1998) proposed that valproate induces a metabolic syndrome in women with epilepsy, which results in obesity, hyperinsulinemia, lipid abnormalities, and polycystic ovaries or hyperandrogenism. Replacement of valproate with lamotrigine (Lamictal) in these patients resulted in a significant decrease in body weight and a normalization of serum hormone and lipid levels after six months. After one year, the total number of women with polycystic ovaries decreased from 11 to seven.
Although seemingly reversible, endocrine and metabolic consequences of PCOS may include coronary heart disease, hypertension, diabetes and cancer. The importance of these consequences and their clinical implications have stimulated further investigation of the effect of anticonvulsants on female reproductive function. In addition, clozapine (Clozaril) and olanzapine (Zyprexa) have been implicated in glucose dysregulation, although head-to-head studies are lacking.
Thus far, an association between treatment of bipolar disorder (BD) and reproductive endocrine function has not been established (O'Donovan et al., 1999). Retrospective chart reviews in 189 women indicated that treatment with valproate did not appear to be a risk factor for the development of PCOS in patients with BD (Sachs, unpublished data).
We investigated reproductive function in 22 female outpatients, ages 18 to 45, who were taking lithium or divalproex sodium (Depakote) for a DSM-IV diagnosis of BD (Rasgon et al., 2000). We did not find any biochemical or radiological (ultrasound) evidence of PCOS in this sample, unlike Isojrvi et al. (1993). In that 1993 study, the length of exposure to divalproex was approximately seven years, compared to approximately three years in our study. The mean dose for bipolar patients in our study, however, was somewhat higher than in women with epilepsy in the 1993 Isojrvi et al. study.
It is possible that PCOS-like changes occur in association with divalproex sodium only after years of exposure, and a false negative result was obtained in the current study due to a relatively short length of exposure and small sample size. Alternatively, the PCOS-like changes in the epilepsy group could be due to epilepsy per se, or a therapy-epilepsy interaction. The impact of both length and timing of exposure to divalproex on reproductive functioning requires further study with larger sample sizes, longitudinal designs and longer lengths of exposure.
In our cross-sectional study, all patients taking lithium and 70% of women taking divalproex sodium reported some type of menstrual dysfunction (Figure 2), which preceded the diagnosis of BD in many cases. Thus, our preliminary findings suggested that women with BD have a high prevalence of menstrual disturbances independent of therapeutic agent used and, in some cases, preceding the onset of BD. Our findings, as well as those of Isojrvi et al. (1993), indicated a need for a longitudinal, controlled evaluation of reproductive function in women taking mood stabilizers.
At this time, we continue to study the prevalence of PCOS in women with BD receiving mood stabilizers across the five sites within the Stanley Foundation Bipolar Network. In addition, we have started a longitudinal, two-year study of the effects of mood stabilizers and atypical antipsychotics now used in the treatment of BD on metabolic (body mass index, insulin resistance) and female reproductive endocrine function. This study will help to identify the population at risk for the development of endocrine dysfunction and metabolic disturbances upon treatment with mood stabilizers and atypical antipsychotics.
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