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Keywords:

  • bipolar disorder;
  • eating disorder;
  • hormones;
  • menstrual abnormalities;
  • polycystic ovary syndrome;
  • reproductive function;
  • women

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Disclosures
  8. References

Objectives

The purpose of the present study was to investigate the reproductive function of women with bipolar disorder (BD) compared to healthy controls.

Methods

Women diagnosed with BD and healthy controls with no psychiatric history, aged 18–45 years, were recruited from a university clinic and surrounding community. Participants completed a baseline reproductive health questionnaire, serum hormone assessment, and ovulation tracking for three consecutive cycles using urine luteinizing hormone (LH)-detecting strips with a confirmatory luteal-phase serum progesterone.

Results

Women with BD (n = 103) did not differ from controls (n = 36) in demographics, rates of menstrual abnormalities (MAs), or number of ovulation-positive cycles. Of the women with BD, 17% reported a current MA and 39% reported a past MA. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone levels were higher in controls (p = 0.052 and 0.004, respectively), but there were no other differences in biochemical levels. Medication type, dose, or duration was not associated with MA or biochemical markers, although those currently taking an atypical antipsychotic agent indicated a greater rate of current or past MA (80% versus 55%, p = 0.013). In women with BD, 22% reported a period of amenorrhea associated with exercising or stress, versus 8% of controls (p = 0.064). Self-reported rates of bulimia and anorexia nervosa were 10% and 5%, respectively.

Conclusions

Rates of MA and biochemical levels did not significantly differ between women with BD and controls. Current atypical antipsychotic agent use was associated with a higher rate of current or past MA and should be further investigated. The incidence of stress-induced amenorrhea should be further investigated in this population, as should the comorbid incidence of eating disorders.

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 (MAs) 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 both by 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 antipsychotic agents (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 varied in the 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 in total testosterone over time 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. The present 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 those in a control group of healthy women with no psychiatric history.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Disclosures
  8. References

Participants

Women with BD between the ages of 18 and 45 years were recruited from the Center for Neuroscience in Women's Health and the Bipolar Disorders Clinic in the Department of Psychiatry and Behavioral Sciences at Stanford University Medical Center (Stanford, CA, USA), as well as from the surrounding community using fliers, advertisements in local newspapers, and through the registry of federally supported clinical trials (http://clinicaltrials.gov). Control subjects were recruited from the community using fliers and advertisements in local newspapers referencing a study on reproductive function. Control subjects with any history of psychiatric illness or history of ever having received psychotropic medication were excluded from the study. Exclusion criteria for all participants included illicit drug use in the previous six months; uncontrolled medical conditions; being peri- or post-menopause [as indicated by follicle stimulating hormone (FSH) ≥ 40 mIU/mL]; hormonal contraceptive use within the previous three months; current pregnancy, breast-feeding, or plans to get pregnant; endocrine disease (i.e., diabetes, hypothyroidism); or a mood disorder secondary to a general medical condition. Diagnosis of BD was confirmed via administration of the Structured Clinical Interview for DSM-IV Diagnoses (SCID). Women with BD receiving psychotropic medication were required to have stable medications for at least three months prior to baseline evaluation.

Enrollment numbers for the study called for a 2:1 ratio of women with BD to healthy control subjects based on preliminary reproductive endocrine findings [11, 33] and a high projected rate of drop-out for women with BD. A total of 278 women with BD and 52 healthy female control subjects underwent an initial telephone screen for eligibility. Forty women (14%) with BD declined to participate further and 102 (37%) failed telephone screening (32 due to unstable medications, 14 due to suicidal ideation, eight due to uncontrolled medical conditions or endocrine disease, 21 due to recent illicit drug use, 23 due to current breastfeeding or plans to get pregnant, and four due to perimenopausal status). There were four (8%) healthy female control subjects who declined participation and eight (15%) who failed telephone screening (two due to psychiatric history, three due to plans to get pregnant, two due to recent illicit drug use, and one due to endocrine disease). Thus, 136 women with BD (49%) and 40 controls (77%) were consented into the study. A total of 121 women with BD (89%) and 38 controls (87%) completed the baseline intake evaluation and questionnaires, and 103 women with BD (76%) and 36 controls (90%) completed the assessment of metabolic function (see Fig. 1).

image

Figure 1. Enrollment and attrition. BD = bipolar disorder.

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Procedures

All study evaluations took place at the Center for Neuroscience in Women's Health within the Department of Psychiatry and Behavioral Sciences at Stanford University Medical Center and at the Clinical Trials Research Unit (CTRU) at Stanford Hospital. After providing verbal and written informed consent, all subjects underwent the SCID to verify the psychiatric diagnosis of BD and to rule out psychopathology in control subjects. Assessment of eligibility also included a baseline screen of serum markers including FSH, thyroid function markers [thyroid-stimulating hormone, triiodothyronine, and thyroxine], fasting insulin and glucose, and mood stabilizer (MS) levels to assess medication compliance; a urine toxicology screening and a urine human chorionic gonadotropin test to rule out pregnancy; and the collection of a medical history to rule out uncontrolled medical conditions. Detailed information was collected from all patients with BD regarding current and previous psychotropic treatment. Where available, these data were cross-checked with clinic charts to ensure validity. Participants were required to notify study personnel of any medication changes.

After confirmation of eligibility, a trained clinical interviewer rated each subject on the Montgomery–Åsberg Depression Rating Scale (MADRS) [35] and the Young Mania Rating Scale (YMRS) [36] to assess the severity of current depressive and manic symptoms, and additional baseline data were collected, including assessment of height, weight, and waist circumference; clinical assessment of hirsutism using the Ferriman–Gallwey scale [37]; and serum levels of bioavailable, free, and total testosterone; sex hormone binding globulin (SHBG); estradiol and estrone; luteinizing hormone (LH); FSH; 17-hydroxyprogesterone (17-OHP); dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS); prolactin; early morning fasting plasma glucose (FPG) and insulin (FPI). Glucose was measured using the glucose oxidase method on a YSI glucose analyzer (YSI Life Sciences, Yellow Springs, OH, USA), while the remaining serum markers were measured using the radio-immunoassay method by Diagnostic Systems Laboratories. PCOS was determined by the Revised 2003 Rotterdam criteria using self-reported information on oligomenorrhea and amenorrhea, the clinical Ferriman–Gallwey score, and the biochemical assessment of hyperandrogenism (free and total testosterone). When self-reported data regarding polycystic ovarian morphology on ultrasound were available, this was also used. A detailed analysis of metabolic parameters in this sample –including body mass index (BMI), waist circumference, FPG, and FPI – are presented elsewhere [24].

Subjects then completed three consecutive months of ovulation tracking using daily urine LH-surge ovulation tracking kits (American Screening Corporation, Shreveport, LA, USA) starting on Day 8 of their menstrual cycle. Subjects with a detectable LH surge underwent a midluteal phase confirmatory blood draw assessing progesterone five to seven days post-LH surge. Patients without a detectable LH surge underwent a progesterone blood draw between Days 19 and 21 of their menstrual cycle. For patients with amenorrhea or without a regular menstrual cycle, three consecutive monthly blood draws on the same day each month were obtained to assess progesterone. The study was approved in its entirety by the Stanford University Administrative Panel on Human Subjects. Subjects provided written and verbal informed consent prior to participation.

Statistical analysis

Statistical analyses were performed using SPSS software version 18.0 (SPSS, Inc., Chicago, IL, USA). All statistical tests were two-tailed and conducted at the 0.05 significance level. Statistical trends ≤ 0.10 were also noted. Univariate analysis of variance (ANOVA) and chi-square analyses were conducted to compare continuous and categorical data between BD and control participants as well as within subgroups of women with BD. Linear regression modeling was used to assess predictors of MA status and biochemical levels. Pearson correlation scores were used to assess correlation between continuous variables such as BMI and biochemical levels.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Disclosures
  8. References

Demographic and clinical characteristics

Demographic and clinical characteristics for women with BD versus healthy controls are shown in Table 1. Women with BD did not significantly differ from healthy control participants in terms of age, years of education, distribution of ethnicity, marital status, or parity. Predictably, MADRS and YMRS scores were significantly higher for women with BD. Women with BD had a mean age at diagnosis of 26.8 years (range 9–41) and recorded a mean age at symptom onset (first depressive, manic, or hypomanic episode) of 15.8 years (standard deviation = 5.7, range 5–30). Rates of past use of oral contraceptives were similar between the two groups (90% in women with BD, 81% in controls).

Table 1. Demographic and clinical characteristics of women with bipolar disorder and healthy controls
 Bipolar disorder (n = 103)Controls (n = 36)p-value
  1. AAP = atypical antipsychotic agent; BD = bipolar disorder; MADRS = Montgomery–Åsberg Depression Rating Scale; MS = mood stabilizer; N/A = not applicable; NOS = not otherwise specified; NS = not significant; SD = standard deviation; YMRS = Young Mania Rating Scale.

Age, years, mean (SD)31.9 (6.7)31.3 (7.4)NS
Education, years, mean (SD)15.8 (1.7)16.1 (1.7)NS
Ethnicity, n (%)
Caucasian82 (79.6)26 (66.7)NS
Asian/Pacific Islander9 (8.7)5 (13.9)NS
Hispanic10 (9.7)4 (11.1)NS
African-American2 (1.9)3 (8.3)NS
Marital status, n (%)
Single/divorced51 (49.5)22 (61.1)NS
Married or living with partner52 (50.4)14 (38.9)NS
Parity, mean (SD)0.45 (0.87)0.45 (0.81)NS
MADRS score at study entry, mean (SD)10.6 (8.7)1.9 (2.9)p < 0.001
YMRS score at study entry, mean (SD)4.7 (4.5)1.2 (1.9)p < 0.001
Age at BD diagnosis, years, mean (SD)26.8 (6.6)N/A 
Type of BD, n (%) N/A 
BD type I37 (35.9)  
BD type II40 (38.8)  
BD NOS24 (23.3)  
Duration of MS/AAP use, months, n (%) N/A 
< 3 months17 (16.5)  
3–6 months16 (15.5)  
6–12 months20 (19.4)  
12+ months33 (32.1)  
No MS/AAP in past 6 months15 (14.5)  

Approximately three-quarters of patients with BD were euthymic at baseline evaluation using MADRS and YMRS scores (data not shown). Clinically significant depressive symptoms (MADRS score ≥ 20) were observed in 17.8% of women with BD. Clinically significant hypomanic symptoms (YMRS score between 12 and 19) were observed in 7.7% of women with BD, and clinically significant manic symptoms (YMRS score > 20) were observed in 1.1% of women with BD.

Among women with BD, 43% were receiving MS monotherapy, 15% AAP monotherapy, 25% MS + AAP combination therapy, and 7% antidepressant monotherapy, while 7% had been medication free for at least six months prior to study entry. Only two women with BD were completely treatment naïve at study entry. MSs included VPA, lithium (Li), carbamazepine, oxcarbazepine, and lamotrigine (LTG). Ten women with BD were receiving VPA, four of whom as a monotherapy. By contrast, 17 women with BD were receiving Li, nine of whom as a monotherapy.

Menstrual history questionnaire data

Questionnaire data regarding menstrual history and abnormalities in women with BD versus healthy controls are presented in Table 2. Reported rates of MA, defined as oligomenorrhea (fewer than eight cycles in 12 months) or amenorrhea (no cycles for at least one year) did not differ between BD and controls. Among women with BD, 17% reported a current MA, 39% reported a past history of oligomenorrhea or amenorrhea but no current MA, and 36% reported no history of or current MA. Notably, of the 54 participants with BD who indicated a past or current MA, 23 (42.6%) reported a MA before diagnosis of BD. Similarly, of the 14 women with BD reporting a current MA, nine (64.3%) indicated having an MA before BD diagnosis. Five women with BD (4.7%) qualified for a diagnosis of PCOS using the Revised 2003 Rotterdam criteria, while none of the control subjects qualified (Table 2).

Table 2. Menstrual history questionnaire data for women with bipolar disorder and healthy controls
 Bipolar disorder (n = 103)Controls (n = 36)p-value
  1. BD = bipolar disorder; MA = menstrual abnormality; NS = not significant; PCOS = polycystic ovary syndrome; SD = standard deviation.

  2. a

    Mann–Whitney U-test.

Self-reported MA, n (%)
No current or past history of MA64 (62.0)27 (75.0)NS
History of oligomenorrhea8 (7.8)3 (8.3)NS
History of amenorrhea8 (7.8)2 (5.5)NS
Current oligomenorrhea9 (8.7)2 (5.5)NS
Current amenorrhea7 (6.8)2 (5.5)NS
Pre-existing MA prior to BD diagnosis, n (%)26 (25.0)
PCOS diagnosis, n (%)5 (4.8)0 (0)NS
Central amenorrhea, n (%)22 (21.0)4 (11.0)NS
Age at menarche, years, mean (SD)12.44 (1.47)12.38 (1.52)NS
No. of cycles in the last 12 months, mean (SD)11.2 (1.96)11.9 (1.37)0.016a
Menstrual cycle < 25 days, n (%)24 (23.0)9 (25.0)NS
Bleeding > 10 days, n (%)32 (31.0)4 (11.0)0.009
Body mass index, mean (SD)27.5 (7.5)24.8 (5.1)0.035

Among controls, the incidence of current MA was 4%, a history of MA was 34%, and no current or past MA was 53%. Subdivisions of oligomenorrhea and amenorrhea are further compared in Table 2, as well as additional data querying whether participants had experienced menstrual cycles shorter than 25 days or menstrual bleeding greater than ten consecutive days. These rates did not significantly differ between BD and controls, although there was a trend toward more women with BD experiencing greater than ten days of menstrual bleeding (p = 0.009). Mood rating scores on the MADRS and YMRS did not differ significantly between MA groups.

History of MA (either past or current) was also compared between types of BD [type I, type II, not otherwise specified (NOS)]. Thirty out of 37 women (81%) with BD type I indicated a current or past MA, versus 25 out of 38 women (66%) with BD type II, and 13 out of 22 (59%) women with BD NOS; however, these differences were not statistically significant (p = 0.154). Current or past history of MA was not associated with clinically assessed weight, BMI, scores on MADRS or YMRS, age at diagnosis of BD, age at first manic episode, or age at first depressive episode.

Seven women with BD self-identified on the questionnaire as having been diagnosed previously with anorexia nervosa, while ten self-identified as having been diagnosed with bulimia nervosa. In women with BD, 21 out of 96 women (22%) marked that they had experienced a period of time during which they had stopped having periods due to stress or exercise, versus three out of 37 controls (8%) (p = 0.064).

Ovulation tracking

Regarding ovulation tracking data, 59 of the 103 women with BD underwent at least one month of luteal progesterone assessment to evaluate ovulation. Of these 59, 50 underwent two consecutive months and 48 three consecutive months of testing. By comparison, 33 of the control women underwent testing during the first month, 30 undergoing two consecutive months and 28 three consecutive months (see Fig. 1). For the purposes of comparison between BD and controls, the five women with diagnosed PCOS were excluded from analysis. Data regarding the rate of ovulation are presented in Table 3 and did not differ between BD and controls. Ovulation tracking data were also aggregated by current MA, past MA, or no history of MA. Among those with BD, 57% of those reporting a current MA demonstrated two ovulatory cycles, compared to 86% of those with a past MA and 94% of those with no MA; however, cell sizes were small and statistical analysis did not find any significant difference between these rates. In control women, all three women who indicated a current MA had two ovulatory cycles, compared to 90% of those with a past MA and 81% of those with no MA.

Table 3. Ovulation tracking data in bipolar disorder and healthy controls
 Bipolar disordera (n = 59, 50, 48)Controlsa (n = 33, 30, 28)p-value
  1. NS = not significant.

  2. a

    n includes all women (except those with polycystic ovary syndrome) who obtained ovulation data for one, two, and three consecutive cycles, respectively.

  3. b

    n total = number of women with at least two cycles of data, minus women with only two cycles of data that were split between one positive and one negative result.

Positive ovulation during, n (%)
First cycle38 (64)25 (76)NS
Second cycle45 (90)25 (76)NS
Third cycle35 (73)19 (68)NS
Positive ovulation for at least two cycles, n/n total (%)b43/48 (89)25/27 (92)NS
Positive ovulation for all three cycles, n (%)20 (42)11 (39)NS
No. who did not ovulate at all or only ovulated 1/3 consecutive cycles, n (%)9 (19)4 (14)NS

Biochemical data

Data comparing the biochemical levels of reproductive hormones between those with BD and healthy controls are presented in Table 4. Values were not significantly different except for DHEAS (higher in controls, p = 0.052) and 17-OHP (higher in controls, p = 0.004). Biochemical data were further compared among women with BD by MA status (current, past, none) and BD diagnosis (type I, type II, and NOS) (data not shown). In comparing the three MA subgroups, the LH:FSH ratio was notably highest in those with a current MA, and lowest in those with no such history (p = 0.046). Similarly, SHBG was lowest in those with no history of MA, but there was no different between those with current and with past MA (p = 0.010).

Table 4. Biochemical data in women with bipolar disorder and healthy controls
 Bipolar disorderControls 
 Mean (SD)NMean (SD)Np-value
  1. 17-OHP = 17-hydroxyprogesterone; DHEA = dehydroepiandrosterone; DHEAS = dehydroepiandrosterone sulfate; FSH =follicle-stimulating hormone; LH = luteinizing hormone; NS = not significant; SD = standard deviation; SHBG = sex hormone binding globulin.

Prolactin11.2 (8.4)7712.6 (7.2)32NS
Estradiol44.2 (32.7)7838.8 (17.9)34NS
LH5.6 (2.9)785.1 (2.0)33NS
FSH7.3 (6.1)776.7 (1.8)34NS
FSH/LH ratio0.9 (0.5)770.8 (0.3)33NS
Estrone53.6 (17.8)7354.6 (17.9)33NS
DHEAS180.8 (98.9)76221.2 (102.0)340.052
Free testosterone3.7 (6.6)763.0 (2.1)34NS
Total testosterone31.5 (47.1)7623.0 (12.1)34NS
SHBG57.6 (32.3)7153.2 (28.3)34NS
17-OHP61.9 (48.8)7690.1 (40.7)340.004
DHEA9.1 (7.1)679.7 (6.8)32NS

When comparing biochemical data by BD diagnosis, significant differences were noted in DHEAS and 17-OHP. DHEAS was significantly higher in BD type I and BD type II when compared to BD NOS (200 ± 117.0, 187 ± 97.2, and 137 ± 49.2, respectively; p = 0.013). Similarly, 17-OHP was noted to be highest in BD type I and lowest in BD NOS (the three respective values for BD type I, BD type II, and BD NOS being 66.0 ± 56.6, 63.7 ± 51.4, and 53.1 ± 31.3; p = 0.036).

Data regarding metabolic biochemical parameters and familial history of diabetes are published elsewhere [24]. BMI was not correlated with most biochemical measures, except negatively with SHBG (Pearson correlation −0.234, p = 0.018), a finding that was not mediated by MA history or BD diagnosis. BMI was also not significantly different among the three MA subgroups.

Medication data

The presence and history of MA, number of positive ovulations, and biochemical data were compared between women with BD who had been on psychotropic medication for less than three months (including the two treatment-naïve patients, total n = 32) versus those who had been on psychotropic medications for more than three months (n = 87, three subjects with missing data). Fifty-three percent (n = 17) of those on medications for less than three months indicated no current or past MA, versus only 27% (n = 18) in women on medications for more than three months, although this was not significantly different (p = 0.108). For women with at least two months of ovulation data, 75% (n = 12) of those on less than three months of medication had at least two positive ovulations, compared to 83% (n = 30) of women on medication for more than three months (not significant). Of those with three months of ovulation data, 42% of women with BD on less than three months of medication had three ovulation-positive cycles compared to 40% of those on medications for more than three months (not significant). There were no significant differences in any biochemical markers between treatment duration groups.

In women with BD, MA status (current, past, never), number of positive ovulations, and biochemical data were also compared between those currently or ever on VPA, Li, or an AAP. No differences in MA status or number of positive ovulations were noted between women currently on VPA (versus those who were not) or between women ever on VPA (versus those who were not). Similarly, no differences were noted between the Li treatment groups. However, 80% (20 out of 25) of women who were currently taking an AAP indicated a current or past MA, versus 55% (37 out of 67) of women not currently taking an AAP (p = 0.013). Past use of AAPs was not recorded. Using linear regression, the number of months on AAP did not predict MA status. Ovulation and biochemical data did not differ between those who were currently taking or had ever taken VPA or an AAP compared to those who had not. For women with BD indicating that they were either currently taking or had ever taken Li, mean follicular phase estrone was significantly higher (59.2 ± 17.6 versus 46.2 ± 13.5, p = 0.002), but no other differences were noted. Linear regression indicated that the duration of Li use was not a significant factor.

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Disclosures
  8. References

The reproductive function of women with BD has increasingly become an area of interest, driven by the need to clarify the risks and benefits of medication regimens in order to improve treatment guidelines. However, much remains to be elucidated; for example, few studies describe even baseline levels of reproductive hormones or self-reported MAs in this population, and virtually no studies have compared reproductive indices in women with BD to those in active controls. In addition, it is poorly understood whether reproductive function may be impacted by the pathophysiology of BD itself, perhaps through modulations of the hypothalamic-pituitary-adrenal (HPA) or hypothalamic-pituitary-gonadal (HPG) axes, or through the potential effects of medications used to treat BD, such as VPA, Li, and increasingly AAPs. Pharmacological effects that have been implicated include the possible effect of VPA on testosterone and insulin resistance in the development of PCOS [1, 3-5] and the metabolic effects of AAPs, which may also mediate the development of anovulatory syndromes such as PCOS, although studies remain divided [8-12].

To our knowledge, this is the first published study to have examined reproductive function in women with BD in comparison to a control population. In this clinical sample, the self-reported rate of oligomenorrhea or amenorrhea was close to 40%, consistent with our previously reported rates in a longitudinal evaluation of reproductive function in 25 women with BD (which represented a different sample but used similar enrollment criteria) [32] as well as rates published by others [5, 34]. Also consistent with our 2005 findings, we found that rates of oligomenorrhea and amenorrhea did not differ between treatment groups, including those who had been treated for less than three months or not at all, and that many patients noted an MA that preceded the diagnosis, and therefore the treatment, of BD [32].

It is interesting to note that reported rates of MA in our current study did not necessarily correlate with anovulation as measured by three consecutive monthly luteal-phase progesterone levels, and did not reflect the relatively low rate of PCOS, at around 5%, which matches the normal population rate of 4–6% [20, 21], although few studies reflect the most updated Rotterdam criteria. The majority of patients (almost 90%) had at least two positive ovulations during the consecutive three months, and this did not differ between women with BD and controls, and did not differ significantly by MA status. Notably, only 57% of our participants with BD completed even one month of ovulation tracking, which reflects the feasibility constraints of tracking, liaising, and coordinating with the necessary precision in this population. Although the exact reasons why participants were unable to complete ovulation tracking were not assessed, many of the women with BD in our study were either students or worked part- or full time, presenting significant scheduling difficulties. However, this was similarly true for the majority of our control participants, of whom 92% completed at least one ovulation tracking cycle, which may reflect the unique motivations of the largely self-selected control population. Additionally, there may have been self-selection bias within the control population, given that recruitment efforts made reference to assessment of reproductive function, but the direction of this bias is unclear as reasons to participate in such a study could vary. Although the percentage of women with BD who obtained ovulation tracking data was low, we were able to retain most of these subjects over the three-month tracking period, with an attrition rate of 19%.

It is unclear why self-reported rates of MA – specifically, oligomenorrhea and amenorrhea – do not match up with objectively measured ovulation rates. This may reflect a perceived experience of variability in the menstrual cycle, with a retrospective reporting bias that appears to be similar both in women with BD and in controls, but does not necessarily reflect current ovulatory functioning. This finding points to a future need to assess closely for objective measures of reproductive functioning, such as biochemical ovulation tracking rather than relying on self-reported menstrual cycle questionnaires.

Almost 10% of women with BD self-reported a diagnosis of bulimia nervosa, with 5% reporting a diagnosis of anorexia nervosa. Given that the present study selected a control group without a psychiatric diagnosis, we cannot compare these two populations in our study; however, these data add to a sparse but growing literature on the prevalence of eating disorders in women with BD [38-40]. A recent study by McElroy et al. [41] reported a rate of binge eating disorder in women with BD of 9%, compared to 5% for bulimia nervosa and 3% for anorexia nervosa, with an overall rate of 14.3% for all eating disorders. In the present study, we did not specify between binge-eating disorder and bulimia, but our preliminary rates appear to be similar to these reported rates. They are also similar to rates reported in a subgroup analysis comparing men and women with BD in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, which found significantly higher rates of reported bulimia in women (12%) compared to men (2%) [42]. Further exploration of the intersection of BD and eating disorders is needed, particularly in light of the growing consensus that certain eating disorders may share neurocircuitry with dysregulated impulse control [43].

Twenty-two percent of women with BD indicated that they had experienced a period of time during which they stopped having periods due to stress or exercise, versus 8% of controls, although this represents retrospective self-reported data. This incidence of what is sometimes called hypothalamic or central amenorrhea due to the surmised central role of HPA dysregulation [44] has not, to our knowledge, been reported in the BD population to date. However, these preliminary data suggest that it should be further investigated, particularly as we continue to seek to understand how the HPA and HPG axes function in the context of BD and its pharmacotherapy.

In fact, these rates of self-reported eating disorders and central amenorrhea may help to explain the high rates of reported past MA in the BD population. In particular, if the eating disorder or period of exercise or stress was in the past, resolution of the MA would occur with resolution of the disorder and this may explain why past MA was far more commonly reported than current MA, and even why current MAs were, at times, accompanied by normal ovulation tracking results. However, these aspects of the potential inter-relatedness of eating disorders, central amenorrhea, and BD deserve further careful longitudinal study for clarification.

Interestingly, DHEAS and 17-OH-progesterone were both significantly higher in controls compared to patients with BD. Increased DHEAS and 17-OH-progesterone values, as general indicators of adrenal function, have been associated with states of HPA and HPG dysregulation, such as PCOS [45], although rates of PCOS and MA were not higher in controls. However, given the higher reporting of past central amenorrhea in women with BD than in controls, the lower DHEAS and 17-OH-progresterone values could represent an adrenal ‘burn-out’ scenario in which continued dysregulation at the level of the HPA axis eventually leads to lower adrenal hormone production. This theory remains speculative at this point and further studies are needed to test it.

There has been considerable discussion in the literature regarding whether psychotropic medications, in particular those used as MSs, cause reproductive dysfunction or MAs such as PCOS. The use of VPA has been a particular point of interest, although the metabolic effects of AAPs have also caused growing concern. As reviewed by Joffe and Hayes [46], although many studies have shown an association between VPA use and MAs or biochemical abnormalities, not all have upheld this association. Similar to the results of our previous studies, we did not find any biochemical differences, including in free or total testosterone, between women receiving or not receiving VPA. However, in our previous studies we found that the duration of VPA use was positively correlated with free testosterone levels, something we could not corroborate in the current study. Notably, in the present study we found that a higher percentage of women currently taking an AAP indicated a past or present MA compared to those not on an AAP, suggesting a future area for research as little as been published regarding the use of AAPs and reproductive dysfunction.

Regarding our population sample, clinical and demographic characteristics were similar in many ways to those reported in other large, multi-site studies in the BD population [47], although only one of these large studies completed a subset analysis comparing data by gender [42]. In the latter study, investigators found that the incidence of BD type II was higher in women compared to men (30% versus 16%, respectively), a finding that had been noted in two previous studies but had not reached statistical significance [48, 49]. Rates of BD NOS were not reported [42]. Notably, our percentages of women diagnosed with BD type II and BD NOS were higher than those previously cited, at 39% and 23%, respectively. It is unclear why BD type II and BD NOS patients were more highly represented in our sample, although, given that women with BD generally self-selected to contact the study coordinator for enrollment in our study, it may reflect an increased drive toward study participation in these populations, for unknown reasons. It is important to note that our sample population did not include women with uncontrolled medical conditions or illicit substance use, so the results may not be generalizable to these populations. It is also interesting to note that the stability of our population is both a strength of the study, as it avoids the potential confounding effects of acute affective episodes (either depression or mania), and a weakness, in that we were unable to explore whether changes in our biochemical variables are reflected in acute affective states.

Although the present study was the first to compare reproductive function data in women with BD against a control group of healthy women, it had some limitations, particularly in the size and sampling of the control group, which could have contributed to the lack of differences between groups for some variables. At the same time, the present study included a fairly large sample of women with BD (n = 103). The reason for the unequal numbers of women with BD and control women is that the original proposal was designed with a 2:1 ratio of women with BD to healthy controls for three-month ovulation tracking data as part of the overall metabolic and reproductive aims of the study. Given that a high dropout was projected for women with BD, a much larger number of women with BD underwent baseline function. As noted earlier, the control population was solicited through community advertisements, which led to a self-selected group of women pursuing enrollment, and it is possible that these women represent a unique population with a vested interest in obtaining information about their reproductive functioning, thus posing potential difficulties in generalizability. However, the two groups were notably similar in terms of demographic information.

As in almost all studies of BD, a significant portion of patients with BD were receiving more than one psychotropic medication, and the absence of uniform treatment regimens represents a limitation of the results. Missing data and small cell sizes prevented analysis of some measures, such as AAP dosing and the use of AAPs known to cause prolactinemia. At the same time, the present study is a reflection of the real-life treatment of BD, as no single treatment approach provides adequate outcomes for many of the diverse patients with this illness. It would also be relevant and important to include a measure of trauma history, which was not included in our assessment, given the prevalence of trauma in this population and its potential impact on neuroendocrine axes.

In summary, women with BD exhibit a high rate of current and past MA, but this rate does not appear to differ from the rate in control populations. Further studies investigating MAs should take into consideration the fact that many subjects who subjectively reported oligomenorrhea or amenorrhea had two out of three, if not three out of three, positive ovulations during tracking, suggesting the need for more objective means of measuring menstrual functioning. Medications did not show associations with biochemical markers or objective evaluation of ovulation tracking; however, current AAP use was associated with a higher rate of current or past MA. History of and/or current incidence of central amenorrhea due to HPA dysregulation should be further investigated in this population.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Disclosures
  8. References

Funding for this study was provided by National Institute of Mental Health RO1 grant MH066033.

Disclosures

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Disclosures
  8. References

PW has received grant/research support and/or has been a consultant and/or received lecture honoraria from Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly & Co., GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Novartis, Organon, Otsuka, Pfizer, Repligen, Solvay, Valeant Pharmaceuticals, and Vanda Pharmaceuticals. TAK has received grant/research support and/or has been a consultant and/or received lecture honoraria from Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly & Co., GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Johnson & Johnson, Novartis, Organon, Otsuka, Pfizer, Repligen, Solvay, Valeant Pharmaceuticals, and Vanda Pharmaceuticals. NLR has received grant/research support and/or has been a consultant from Bayer HealthCare, Bristol-Myers Squibb, Forest Laboratories, GlaxoSmithKline, and Wyeth-Ayerst. MFR-M, HAK, WM, and PGS do not have any financial disclosures to report.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Disclosures
  8. References