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Androgens and Mood Dysfunction in Women: Comparison of Women With Polycystic Ovarian Syndrome to Healthy Controls

From the Behavioral and Neuropsychological Consultants (C.L.W.), LLP, New York, NY; Department of Psychiatry (M.P.), Loyola University Medical Center, Chicago, IL; and Department of Medicine (D.A.E.), Section of Endocrinology, University of Chicago Medical Center, Chicago, IL.

Address correspondence and reprint requests to Cindy L Weiner, PhD, Behavioral and Neuropsychological Consultants, LLP 304 Park Avenue S., Suite 1128, New York, NY 10010. E-mail: cweiner{at}bncnyc.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
OBJECTIVE: Our understanding of the organizational and activational effects of human gonadal hormones on behavior has depended on the study of endocrine disorders. Polycystic ovarian syndrome (PCOS) is a hormonal disorder that begins in puberty and is characterized by chronically augmented free testosterone (FT) levels. The purposes of this study were 1) to compare negative mood states of women with PCOS to those of women with normal hormonal levels and 2) to examine the relationship between negative moods and androgens.

METHODS: Twenty-seven women with PCOS were case-matched to 27 normal menstruating women on body mass index since being overweight is a common symptom of PCOS and could affect mood states. Serum levels of FT, total testosterone, sex hormone binding globulin, estradiol, and progesterone were determined. Self-reported depression, anger, anxiety, and aggression were analyzed between groups, and individual scores were compared across groups to hormone values.

RESULTS: Depression was significantly increased in the PCOS group and remained so after considering the variance related to physical symptomatology and other mood states. Furthermore, a curvilinear relationship between FT and negative affect across groups was suggested: the most elevated negative mood-scale scores were associated with FT values just beyond the upper limits of normal, while lower negative mood levels corresponded to both normal and extremely high values of FT.

CONCLUSIONS: These results are consistent with a model of activational influences of testosterone on adult female behavior. Implications are discussed for future research and for treatment of PCOS and other menstrual-cycle mood disorders.

Key Words: polycystic ovarian syndrome, • testosterone, • hormones, • mood, • menstrual cycle, • depression.

Abbreviations: PCOS = polycystic ovarian syndrome;; FT = free testosterone;; BMI = body mass index;; SHBG = sex hormone binding globulin;; PMS = premenstrual syndrome;; VAS = Visual Analog Scale.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
Androgens have different effects on the brain and behavior depending on the timing of exposure during development. Prenatal, and possible early postnatal, exposure can potentially affect the organization of the brain, permanently changing its morphology and subsequent behavioral responses. Activational effects, such as those that occur during puberty, are not believed to permanently change the structure of the brain, although they can produce prolonged physiological effects that influence behavior. Because affective disorders are more prevalent during a woman’s reproductive years than at other times in her life (1–3), it has been theorized that deviant gonadal hormone levels contribute to the manifestation of dysfunctional mood states in women through activational effects in the brain (4,5). Researchers have hypothesized that the hormones alter the form or number of neurotransmitter receptors in the brain, therefore changing sensitivity to endogenous or exogenous conditions, which may provoke mood disorders (6,7).

Augmented levels of androgens have been related to clinical mood disorders in women. For example, increased free testosterone (FT), the bioactive form of testosterone, was observed in women with premenstrual syndrome (PMS) (8,9) and in depressed women (10,11). In contrast, healthy women without PMS were found to have decreased free testosterone levels premenstrually (12). Self-reported negative mood states correlated with testosterone in other stages of the menstrual cycle; testosterone correlated with anger and depression prepartum and postpartum in women (13), and menopausal women administered testosterone or testosterone with estrogen had increased hostility in relation to heightened serum androgen levels (14). In women first identified by abnormally elevated androgen levels, self-reported negative moods, such as depression, hostility, and irritability, were reported to be increased. Examples are hirsute women (15,16), in whom mood was not necessarily related to the degree of symptoms associated with the disorder (16), and women with polycystic ovarian syndrome (PCOS) who reported increased assaultive behavior (17). Anger proneness was observed to increase significantly in female-to-male transsexuals with the administration of testosterone (18). Imprisoned females convicted for unprovoked violent acts had higher FT levels than females imprisoned for defensive violent behavior, eg, killing an abusive husband, and had more disruptive behavior in prison (19). Lastly, testosterone measured serially in nonclinical subjects predicted later anger and tension (20).

While some research suggests that androgens may be related to menstrual cycle-mood disorders and to negative mood states in women, females with PMS or depression have also experienced relief with the administration of testosterone (21–23). Other studies have found no significant difference in androgen levels between women with and without PMS (24,25) or have found lower levels of FT to be associated with negative mood (26). Sherwin (27) showed that self-reported hostility, depression, and anxiety were diminished after administration of androgens in menopausal women. Therefore, conflict exists as to the role that androgen levels may play in the mood states of women. Differences in studies contribute to the discrepancies in that some women were administered androgen to simulate normal levels, while others received high doses or had preexisting elevated androgen levels. Some studies could not rule out a possible organizational effect of abnormal androgens on the brain during prenatal development.

A unique clinical population in which to investigate the activational effects of significantly elevated androgen levels on mood states in adult women is PCOS. The syndrome is characterized by chronically augmented testosterone concurrent with low levels of progesterone and estradiol (28–31). In some PCOS patients, sex hormone binding globulin (SHBG) is significantly decreased, resulting in increased FT (32). Since the syndrome begins in puberty, women with PCOS provide the opportunity to study the activational effects of androgens at abnormal levels in adult females separate, as far as we know, from androgen’s organizational effects.

In the present study, mood states of women with untreated PCOS were compared with those of healthy women. Participants were case-matched on physical criteria related to the syndrome, specifically body mass index (BMI). It was hypothesized that self-reported negative mood-state scores would be significantly higher in the PCOS group than the control group. Furthermore, it was believed that group mood differences would be maintained even after the effect of factors associated with having an illness were considered. It was further predicted that FT levels and negative moods would be positively correlated in PCOS women. Although the mood-and-hormone question is typically addressed by first identifying women with mood disturbances, this study presents an alternative approach by examining the relation between mood and gonadal hormones in women first identified by their documented hormone imbalances.

	METHODS

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Subjects
Patients diagnosed with PCOS were referred from the University of Chicago Hospital Department of Medicine, Section of Endocrinology. A diagnosis of PCOS required 1) the presence of oligo/amenorrhea; 2) hyperandrogenemia, defined by a supranormal plasma free T level; 3) hyperandrogenism, as evidenced by infertility, hirsutism, acne, or androgenetic alopecia; and 4) exclusion of nonclassic 21-hydroxylase deficiency congenital adrenal hyperplasia, Cushing’s syndrome, hypothyroidism, or significant elevations in serum prolactin (2). Women with PCOS diagnosed elsewhere by blood tests also self-referred in response to advertisements.

The control women were recruited from advertisements. Women were accepted for the study if they did not have a history of abnormal mood associated with the menstrual cycle and if they had regular, 25- to 35-day cycles. The controls were individually paired to PCOS patients on BMI to control for biological and psychological factors related to being overweight, a common symptom of PCOS. Subjects were also group matched on age, education, and race. None of the subjects had taken oral contraceptives, psychotropic medication, or any medication that could affect the hormone profile under study for at least 2 months before the study; they were not abusing alcohol or drugs, were not pregnant, and did not have other endocrinological disorders. A self-report of past clinical diagnosis of DSM-IV Axis I disorder was exclusionary except for affective disorder since it is believed that an abnormal hormone profile may contribute to the development of depression.

Sixty-five subjects, 30 with PCOS and 35 controls, had their blood drawn and completed testing. Three women in the control group had FT levels outside the normal population range, defined as above 12 pg/ml, while three PCOS subjects did not exhibit the typical hormonal profile, ie, FT levels below 14 pg/ml. These women were excluded from analyses, resulting in 27 eligible PCOS subjects who were then individually paired on BMI to 27 controls. Fifty-five subjects were tested at the University of Chicago Hospitals Clinical Research Center and 10 women were tested at other clinics. Each subject signed and received a copy of the institutional review board-approved consent form after agreeing to participate in the study. Subjects were told that the purpose of the study was to investigate the relationship between mood states and hormones in women. One of two female clinicians conducted the assessment. Testing required 2.5 to 3 hours because of the administration of other tests as part of a larger study. After completion, subjects were debriefed and paid $25 for their participation.

Hormonal Data
All blood assays were analyzed in the Endocrinology Laboratories of the University of Chicago Hospitals. Plasma concentrations of total testosterone were measured with the Diagnostic Products Corporation commercial kit using radioimmunoassay. Progesterone plasma levels were determined using an in-house (University of Chicago Hospitals) radioimmunoassay after thin layer chromatography (33). The free fraction of plasma testosterone and SHBG was also measured in-house by competitive protein binding assay (34). A Pantex commercial kit was used to measure estradiol levels, using an extraction assay method. Prolactin was evaluated with a double antibody assay, using a commercial kit by Diagnostic Products Corporation. Prolactin was used for screening purposes only since levels above 25 ng/mL can mimic idiopathic PCOS, in which the cause is not known. Each hormone’s reference limits and interassay reliability (coefficients of variation ranging from 8% to 12%) were examined.

Procedures
PCOS women were scheduled for an appointment during the 7th week of their cycle if they had a history of being anovulatory for 2 months at a time. They were tested between days 1 and 8 of the follicular phase if they experienced menses before their scheduled appointment. The control women were scheduled for an appointment between days 1 and 8 of their follicular phase. The follicular phase was chosen because estrogen and progesterone levels in normal women are most similar to those of PCOS patients during this phase. All blood draws were conducted after an overnight fast in order to minimize the variable effects of blood glucose, and before 10 AM to minimize diurnal variation of hormones (35,36). Blood samples for the bioassays of serum estradiol, prolactin, total testosterone, FT, progesterone, and SHBG were collected, centrifuged, frozen, and later analyzed. A standard meal was provided to each subject after the blood draw. Following this, the psychological assessment took place. The questionnaires were administered as follows: Acne Rating Scale (37), demographic questionnaire, Visual Analog Scale (VAS; 6 negative and 4 positive moods were scored along a four inch continuous line and measured in millimeters; (38)), Life Event Questionnaire (39), Eating Disorders Inventory-2-selected subscales (40), Body Image Rating Scale (41,42), Aggression Questionnaire (AQ; 43), State-Trait Anxiety Inventory (STAI; 44), State-Trait Anger Expression Inventory (STAXI; 45), and the State-Trait Depression Adjective Check List (46). A second VAS was completed following the administration of all tests to examine change in mood over time. Weight and height measurements were taken, and a clinician then used the Ferriman and Gallwey (47) criteria to determine the degree of hirsutism. Scores can range up to 40 and are clinically significant if equal to or greater than 6.

Data Analysis
SPSSx statistical program (SPSSx Inc.7.5, 1996) was used to analyze the data. The data were examined for outliers, homogeneity of variance and normality, and corrections were made as appropriate. All hormones other than SHBG were skewed and, therefore, logarithmically transformed. Two-tailed independent t tests and chi-squares were used to examine demographic variables between groups. Paired t tests were used to examine group differences between the women on symptomatology known to be related to PCOS. Variables demonstrating significant differences between groups were used as covariates in MANCOVAs, which were used to examine hypothesized mood differences. Univariate tests followed MANOVAs/MANCOVAs as indicated, therefore taking family-wise error into account. A repeated-measures ANCOVA was used to examine the pretest and posttest VAS scores.

	RESULTS

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Demographics
Twenty-seven pairs of females were individually matched on BMI within 1 point of each other (PCOS mean = 37.70 ± 8.46; control mean = 36.89 ± 7.24, respectively). Age did not significantly differ between the groups (t [52] = 1.21, p = .23); PCOS mean = 28.19 ± 4.84 and control mean = 30.07 ± 6.48. PCOS subjects had 15.44 (±2.36) total years of education, while the control subjects had 14.96 (±2.13) years, a nonsignificant difference, t (52) = 0.79, p = .43. Likewise, the PCOS and control groups did not significantly differ in marital status (x²₁ [N = 54] = 0.09, p = .76), ethnicity (x²₂ [N = 54] = 2.89, p = .24), socioeconomic level (x²₁ [N = 54] = 0.68, p = .41), or the number of years since menarche (t [52] = 1.46, p = .15).

Symptomatology
PCOS subjects had significantly higher amounts of acne (t [26] = 2.59, p < .05) and hirsutism (t [26] = 5.43, p < .001), as expected. However, they also had greater body dissatisfaction, even after adjustment for current BMI (t [26] = 2.75, p < .01), and a larger discrepancy between their ideal body image and how they felt they looked (t [26] = 4.75, p < .001). There were no group differences in overall stress, positive stress or negative stress, binging, or drive for thinness. Symptom intercorrelations reaching the 0.01 level of significance dictated selection of particular symptom variables for covariance in subsequent analyses to prevent redundant partialling of shared variance.

The following scores were used as covariates since they represented different theoretical concepts: 1) adjusted body dissatisfaction, 2) acne, and 3) hirsutism. Additionally, negative stress was used as a covariate since it correlated with many of the mood measures under examination and it was theoretically believed to account for some of the variance in the negative mood states.

Comparisons of Groups on Mood Measures and Hormones
Logarithmically transformed group hormone data are shown in Table 1. Prolactin values in the PCOS group ranged from 1 to 15 with a mean of 6.04 (±4.00) and did not significantly differ from the control group (t [50] = 1.18, p = .24). Table 2 shows the means and standard deviations of all the mood measures for each group. A MANOVA demonstrated that depression significantly differed between the groups (F [2, 51] = 5.49, p < .01). Univariate tests showed that state depression (F [1, 54] = 8.24, p < .01) and trait depression (F [1, 54] = 9.44, p < .01) were significantly greater in the PCOS group. MANCOVAs were then run, demonstrating that depression continued to significantly differ between the groups even after the variance due to other measures of negative affect and symptomatology were taken into consideration (Table 3). The one exception occurred when hirsutism was covaried, resulting in a nonsignificant difference between groups (F [2, 50] = 1.43, p = .25). The MANCOVA was rerun with FT as a covariate to determine if hirsutism uniquely accounted for the group difference or if FT could also account for the difference, since they are highly correlated (r [54] = 0.61, p < .001). A nonsignificant difference was found between the groups when FT was covaried (F [2, 50] = 2.36, p = .11), suggesting that the elevated hormone levels were also related to negative mood.

View larger version (16K): [in this window] [in a new window]   Fig. 1. Curvilinear relationship between Log FT and State Depression for all subjects.

View larger version (19K): [in this window] [in a new window]   Fig. 2. Curvilinear relationship between Log FT and Trait Depression for all subjects.

	DISCUSSION

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The results demonstrated that women with PCOS experienced more state (acute) and trait (long-standing) depressive symptoms than women who have normal hormone levels, consistent with predictions. Elevated FT levels were not related to depression in a simple linear fashion; rather, exploratory analyses of the PCOS and control women together demonstrated that those who were most depressed were the women who had FT levels between 10 and 26 pg/ml, just outside the range of normal. When all subjects were examined, it also became evident that hostility, state anxiety, and trait anxiety were increased at FT levels between 10 and 26 pg/ml but decreased above and below this range. This curvilinear pattern is counterintuitive and calls for replication. If reliable, it does support the argument that the presence of observable physical symptomatology in PCOS alone does not account for elevated negative mood states since women with the highest levels of FT were similar on demographic and symptomatic variables to PCOS women at less extreme levels of FT but did not have the most elevated negative mood. This suggests that the difference in negative mood at different levels of FT is not accounted for by factors such as hirsutism, acne, or age since if hirsutism explained depression, then one would not expect depression to vary significantly at similar, clinical levels of hirsutism. In essence, these analyses separate the "hormonal effect" from the "psychological effect."

It is possible that the reason the moods tended to moderate at the most extreme levels is because of adjustments in the number of receptor binding sites or in the levels of other neurotransmitters. For instance, the exaggerated mood changes of teenagers has been attributed in part to the irregular fluctuation as well as the increase of hormones found at this time, levels to which the adolescent eventually becomes accustomed (48). Perhaps the women at the highest levels of FT in the PCOS group have a more severe form of the disorder and cycle less often than women at lower levels of FT; it is possible that they could have become accustomed to the higher levels of FT. However, when we compared the PCOS women with FT between 14 and 26 pg/ml to those with 26 pg/ml or higher no differences were found in the number of days since last menses. Women at the more extreme levels of FT actually tended to have the disorder for a somewhat shorter period of time (13 vs. 17 years). Studies with larger samples could elucidate whether this pattern of decreased negative affect with unusually high FT levels is reliable.

Women might naturally be more depressed as a result of having an illness and experiencing its associated symptoms. However, case-matching the women on BMI controlled for the psychological effects of being overweight. Rating symptomatology such as hirsutism and acne allowed for the consideration of their effect on the mood states and provided an opportunity to examine the unique contribution of FT to mood state variance. Additionally, demographic factors such as age, education, and ethnicity were group matched to control for the potential effects they could have on the hormone-mood relationship. Choosing controls who had normal menstrual cycles without an associated menstrual cycle-mood disorder and who were evaluated during the first week of the follicular phase provided a comparison group that best simulated the levels of the "female" hormones in the patient group. These methods helped to isolate the potential activational effects of postpubertally elevated androgens. However, since the women knew that the study was examining the relationship between mood states and hormones, a labeling effect may have occurred. The present study sampled blood at one time period. Future investigators would want to consider monitoring women’s moods and hormones longitudinally, especially to track treatment effects. Analyses may also take into account the ratios of androgens, estrogen, and progesterone since research has shown that hormones can have modulating effects on each other. Lastly, curvilinear relationships were conducted post hoc after unexpected relationships were found between hormones and mood in the PCOS group. Additional research is needed with the thought in mind that curvilinear relationships may be present.

In conclusion, this study demonstrated that a relationship exists between androgen levels and negative mood states, particularly depression. Free testosterone in particular showed an association with negative mood beyond its shared variance with hirsutism. Androgens have mainly been thought of as "male" hormones, but should be examined in women who present with affective complaints related to the menstrual cycle with the expectation that levels just outside the upper range of normal may be most highly associated with negative mood states. Specifically for women with PCOS, physicians should be aware that depression might be a symptom of the hormone imbalance, as much as it is in other endocrine disorders such as thyroid disease. Treatment for PCOS is already geared at reducing the androgen levels or blocking their effects. Assessing change in emotional symptomatology as well as physical symptomatology is recommended as part of patient care.

	ACKNOWLEDGMENTS

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Funding from NIH-USPHS GCRC MO1 RR00055, University of Chicago Medical Center, Clinical Research Center; American Psychological Association Dissertation Award; and VA Pittsburgh Healthcare System.

Received for publication September 8, 2003.

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