Arch Gen Psychiatry. 2001 Mar;58(3):297-302.
Decreased cortisol levels in adolescent girls with conduct disorder.
Pajer K, Gardner W, Rubin RT, Perel J, Neal S.
Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 O’Hara St, Suite 430, Pittsburgh, PA, USA.
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BACKGROUND: Female adolescent antisocial behavior is increasing, but little is known about the neuroendocrinologic aspects of this disorder. On the basis of reports of decreased cortisol levels in antisocial males, we investigated morning plasma cortisol levels in adolescent girls with conduct disorder (CD). METHODS: Three plasma samples for cortisol levels were taken every 20 minutes between 8 and 9 AM in 47 adolescent girls with CD (mean +/- SD age, 16.5 +/- 0.9 years) and 37 normal control girls (mean age, 16.0 +/- 0.8 years). All blood was drawn within 72 hours after the onset of menstrual flow. RESULTS: Girls with CD had significantly lower cortisol levels than girls in the normal control group at all 3 sampling times. This finding was not due to procedural factors, demographic characteristics, or the use of medications. The girls with CD who had no other psychiatric problems had lower cortisol levels than girls with other disorders or those in the normal control group. In the multiple regression analysis, having CD predicted 10% of the variance in cortisol levels. CONCLUSIONS: Morning plasma cortisol levels were significantly diminished in adolescent girls with CD. Decreased cortisol levels appear to be most strongly associated with antisocial girls who do not have other psychiatric disorders.

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Introduction

Female adolescent antisocial behavior is prevalent, whether defined as conduct disorder (CD) or delinquency. Conduct disorder is the second most common diagnosis given to adolescent girls,1 and one third of adolescent female psychiatric patients receive the diagnosis.2 In the general population, nearly 10% of 15- to 17-year-old girls meet criteria for CD.3,4

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Unfortunately, current treatments for female antisocial behavior are ineffective.9,10,11,12,13,14,15 Treatments may fail, in part, because little is known about biological correlates of female antisocial behavior. All previous research on neuroendocrinologic function in antisocial disorders has studied males.

One of the most provocative neuroendocrinologic abnormalities reported in antisocial males is decreased cortisol secretion. Low plasma cortisol levels in response to experimental stressors was first described among adult male criminals referred to a maximum-security hospital.16 These men were more violent than a criminal control group, who responded normally to the stressors with an increase in cortisol levels. Ninety-three percent of these hyporesponders had histories of repeated physical violence. Sixty-seven percent of the hyporesponders had committed murder, compared with only 14% of the criminal control group. Similarly, Virkkunen17 found that violent male criminals had decreased cortisol secretion, but that cortisol levels were normal in nonviolent criminals and noncriminal violent men.

Antisocial behavior in boys has also been associated with low resting cortisol levels, especially in boys exhibiting physical aggression.18,19,20 Similarly, both resting salivary cortisol levels and the cortisol response to psychological stimuli were negatively correlated with symptoms of CD in aggressive and impulsive sons of substance-abusing fathers.21,22

Given that low cortisol levels have been found in antisocial males, we investigated whether they are also low in antisocial females. We chose to determine morning cortisol levels because cortisol secretion follows a circadian rhythm and secretion peaks in most people between 8 and 9 AM.23 We focused on teenage girls who were in the final stage of puberty, and who met criteria for repeated antisocial behavior.

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CD vs NC differences in plasma cortisol

Mean plasma cortisol levels were significantly lower in the CD group at all 3 time samples (Figure 1). A repeated-measures analysis of variance was performed, and the effect of group status was significant: F1,82 = 8.40, P = .005. Results of t tests on log-transformed cortisol variables, which included corrections for unequal within-group error variances, showed t71.3 = 2.13, P = .04 at time 0; t75.8 = 2.74, P = .008 at time 1; and t78.4 = 3.08, P = .003 at time 2. The fractional degrees of freedom reflect corrections for unequal variance. Results were similar when the analysis was repeated without the girl who was pregnant. They were also similar when analyses were repeated without a girl who took lithium carbonate, a girl who took sertraline hydrochloride, girls who took oral contraceptives, girls who took medroxyprogesterone, and girls with PTSD. The effect sizes were substantial: time 0, d = 0.48; time 1, d = 0.61; and time 2, d = 0.67; where d = (CD - NC)/SDpooled. Cortisol level was not significantly associated with age, ethnicity, socioeconomic status, or use of oral contraceptives.

To control for NC vs CD differences on other variables that might affect cortisol level, we estimated propensity scores to summarize these differences (see above). We then computed a linear regression of time 2 cortisol level on CD vs NC group status and the propensity score. In this regression, belonging to the CD group lowered cortisol level by 185.1 nmol/L (t81 = 2.53; P = .01), despite our having controlled for the group differences represented by the propensity score.

Plasma cortisol: aggression and psychiatric comorbidity

Thirty-seven girls met the criteria for aggressive CD, with the number of aggressive behaviors ranging from 1 to 10 (mean and median, 3 behaviors). The mean of the plasma levels of cortisol in the aggressive CD group (n = 37) was 336.9 ± 173.5 nmol/L compared with a mean of 386.5 ± 102.6 nmol/L in the nonaggressive CD group (n = 10). However, this difference was not statistically significant (t45 = 1.92; P = .07).

To determine whether decreased cortisol level was simply a correlate of severe psychopathology, as manifested by multiple diagnoses, we examined the mean cortisol levels in the following groups: NC (n = 37) (467.4 ± 212.2 nmol/L), CD with no comorbidity (n = 12) (291.9 ± 131.6 nmol/L), CD with ODD only (n = 6) (338.8 ± 103.2 nmol/L), and CD with multiple diagnoses (n = 29) (372.2 ± 179.1 nmol/L). It is clear that the girls with CD who had no comorbidity, not the girls with multiple comorbid diagnoses, had the lowest mean cortisol level. Only 2 girls had comorbid PTSD, but their cortisol levels were the lowest 2 in the sample. However, these 2 subjects also met criteria for major depression, separation anxiety disorder, and generalized anxiety disorder.

Comment

This is the first study, to our knowledge, of cortisol levels in antisocial girls. It confirmed our hypothesis that adolescent girls with CD would have lower morning cortisol levels than girls without any psychiatric disorder. Thus, it appears that adolescent antisocial girls may have HPA axis dysregulation similar to that found in antisocial boys and men.

The difference in mean cortisol levels between the CD and NC groups is much larger than those reported in previous studies on males.16,17 Not all researchers have found a negative correlation between cortisol levels and antisocial behavior in boys. Mean plasma cortisol levels drawn for morning baseline levels before a fenfluramine challenge were not different in a mixed group of prepubertal and adolescent boys who had "disruptive behavior disorders" compared with normal controls.43 In 2 samples of boys with attention-deficit/hyperactivity disorder, the majority of whom had comorbid CD or oppositional defiant disorder, urinary free cortisol levels44 and plasma cortisol levels45 were no different than levels in NC subjects. However, all of these samples were composed of boys spanning the age range from latency to adolescence and who had been selected on the basis of disruptive behavior or attention-deficit/hyperactivity disorder, rather than repeated acts of antisocial behavior. Our more robust effect may be due to our sampling strategy, which selected a homogeneous group of late-adolescent girls who were in Tanner stage V and who had exhibited a pattern of repeated antisocial acts for at least 1 year. Our design further limited intersubject variance secondary to sampling time and menstrual cycle effects by standardizing these factors across subjects. However, it is also possible that the difference in cortisol levels between antisocial and normal subjects may be more pronounced in females because normal women have higher basal and reactive levels of cortisol than do normal men.46,47,48

The girls with CD displayed substantial psychiatric comorbidity, a finding consistent with other reports in the literature.49,50,51,52 Nonetheless, we were able to demonstrate that the relationship between cortisol level and CD was not simply a reflection of severity of psychopathology, because subjects without other diagnoses actually had the lowest mean cortisol levels.

The finding that antisocial females have low cortisol levels raises important clinical questions. First, low cortisol levels may put these girls at risk for later autoimmune diseases, some types of atopic illnesses, increased inflammation, and infections with extracellular pathogens.53,54,55,56,57,58,59,60,61 This may partially explain the poor adult health of women who had been antisocial adolescents.8,62,63,64,65,66

Second, low cortisol level may be a diagnostic marker for subtypes of girls with CD. To determine whether a biological correlate of a behavioral syndrome is a diagnostic clinical marker, one must first show that the relationship between the two is not due to a confounding factor. We have extended the previous work in males by demonstrating that the association between cortisol and CD is not due to factors such as season or race. The next step is to demonstrate that the biological finding discriminates between subgroups within the spectrum of a diagnostic category.67,68 We did find that girls with aggressive CD had lower mean cortisol levels than girls with nonaggressive CD did, but this difference was not statistically significant. However, only 10 girls with CD were not aggressive. Thus, the question of whether low cortisol level is a marker for aggressive CD in girls remains unanswered.

On the basis of a study reporting a high rate of PTSD in a sample of incarcerated adolescent females69 and data suggesting low cortisol levels in subjects with PTSD,41 we also investigated whether low cortisol level was a marker for antisocial girls with PTSD. The girls with CD with comorbid PTSD had the lowest cortisol levels in our sample, but there were only 2 of them and they also met criteria for several other diagnoses. Furthermore, the NC vs CD differences remained when these 2 cases were deleted from analyses. This important issue should be addressed in a study with larger numbers of antisocial girls with PTSD.

Our design permitted us to examine many alternative explanations for the group difference in cortisol levels. One limitation of our study, however, is that we could not exclude sleep disturbance as an explanation for the difference between the CD and NC groups. If the girls with CD are less well supervised and their lives more chaotic, it is possible that, as a group, they may routinely go to sleep later than midnight. This could shift their circadian rhythm such that the 8 to 9 AM blood-drawing time may still be in the prepeak phase of their HPA axis cycle.70 This question merits further research.

To date, there have been no studies of the mechanisms underlying decreased cortisol levels in antisocial subjects. However, animal and human data suggest that the ratio of corticotropin-releasing hormone to arginine vasopressin may be lower than normal in aggressive subjects, particularly in animals who have been bullied and become bullies themselves.71,72 This explanation may account for both the aggression and PTSD aspects of our findings. Although this research has focused on males, one clinical study of pregnant teens did report that the girls with CD had lower plasma levels of corticotropin-releasing hormone than the pregnant controls without CD.73

Future studies on HPA axis function in these girls should focus on describing the basal state of cortisol secretion throughout the rest of the 24-hour cycle, determining if their HPA axis responds normally to experimentally induced stressors, and methodically investigating the function of each component of the HPA axis (eg, response to corticotropin-releasing hormone, assessment of glucocorticoid receptor function). Research on potential mechanisms may result in more effective pharmacologic interventions or facilitate the identification of subgroups of girls with CD who respond to different types of treatments.

Categories: 2001, Endocrine, Neurosteroids, Adrenal, Cortisol, Behavioral, Conduct disorder, Antisocial behavior, Aggression, Violence, Corticotropin-releasing hormone, HPA axis, Arginine vasopressin