What is CAH?>>Carriers
Endocrinologic and Psychologic Evaluation of
Deborah P. Merke, M.D. and Julie Hardin, B.A.
21-Hydroxylase Deficiency Carriers
Everyone has two 21-hydroxylase genes (one from their mother, one from their father). In autosomal recessive conditions, like CAH due to 21-hydroxylase deficiency, the disease state occurs when both genes are impaired. The carrier state is when a deletion or mutation is present in one of the two genes (one gene is impaired and the other gene is functioning normally). Typically the carrier state is a benign healthy state that goes undetected. Previous studies have shown that carriers of 21-hydroxylase deficiency have subtle differences in the control of their adrenal glands.
The 21-hydroxylase enzyme is important in the production of cortisol. Cortisol is not an independently acting hormone; it is dependent upon a cascade of hormones that precede it in a pathway initiated by the hypothalamus, a brain structure. The hypothalamus is responsible for the production of corticotropin releasing hormone (CRH), which is produced in response to many types of stress. Once released, CRH travels from the hypothalamus to its target, the pituitary gland, where it in turn stimulates the release of adrenocorticotropic hormone (ACTH). As the name implies, ACTH is responsible for stimulating the outside region of the adrenal gland (the cortex) in order to produce cortisol, which is then released into the bloodstream. Cortisol is able to disrupt this linear pathway of hormone stimulation and release by feeding back to the hypothalamus and pituitary to inhibit the production of CRH and ACTH. Thus, this cortisol pathway is self-regulating. If there is an excess amount of cortisol, it will essentially "tell" the hypothalamus and pituitary to quit releasing CRH and ACTH until cortisol levels return to normal.
Previous studies of carriers have found that after ACTH is stimulated, there is an increase in the concentration of substances that build up to cortisol like 17-hydroxyprogesterone. This indicates that many carriers may not be efficiently synthesizing cortisol and may compensate by producing excess amounts of CRH. Oversecretion of CRH has been found in states of anxiety and depression. We recently studied carriers of 21-hydroxylase deficiency in order to obtain both an endocrine and psychologic profile of these individuals and to investigate associations between the adrenal cortex response to CRH stimulation and psychologic characteristics.
Thirty-four consecutively seen parents of children with the classic form of CAH and 23 parents of children with other chronic endocrine disorders were interviewed for entry into the study. The group of control subjects was comprised of parents of children with Turner Syndrome, Cushing disease, and one adoptive parent to a child with CAH. Parents of patients with CAH were excluded from the study due to an associated medical or psychiatric condition more often than the controls (see Table 1). Overall, 18 carriers of 21-OH deficiency (six males and 12 females) were included in the study, along with 16 healthy subjects (five males and 11 females). Because this study is looking at potential vulnerability to stress and anxiety, it was important to have a healthy control group that had also experienced the effects of having a child with a chronic endocrine disorder. None of the subjects that completed the study had a family history of mental illness, were taking medication for a psychiatric problem, or medications that influence the hypothalamus, pituitary gland, or adrenal gland.
The hormonal evaluation included two 24-hour urine specimens to measure urinary free cortisol. On day three of the study, CRH was administered via IV and blood samples measuring ACTH, and 17-hydroxyprogesterone (precursor to cortisol) were collected at –5, 0, 15, 30, and 45 minutes after CRH stimulation.
In terms of the psychologic evaluation, we employed five standardized questionnaires to obtain a psychologic profile of each subject. The assessment included the State-Anxiety Inventory, the Beck Depression Inventory, the Profile of Mood States (POMS), the Symptom Checklist 90-R, and the Temperament and Character Inventory.
The results of the endocrine tests showed that carriers of 21-OH deficiency had significantly lower mean 24-hour urinary free cortisol excretion than the control subjects, but higher ACTH and 17-hydroxyprogesterone levels after CRH stimulation (see Figure 1). The analysis of the psychiatric surveys did not reveal any significant differences between the carrier and control groups.
Because the purpose of this study was to examine associations between hormonal findings and psychologic profiles, we used statistical methods to determine correlations. In carriers of 21-OH deficiency we found a negative correlation between the mean urinary free cortisol excretion and obsessive compulsive behavior, novelty seeking, and reward dependence, meaning that the lower the 24 hour cortisol excretion, the greater the tendency for such behaviors. Likewise there was also a negative correlation between the peak 17-hydroxyprogesterone levels and anxiety and hostility. One should note, however, that these are relationships based on associations, not on cause and effect. For the control subjects, we found a positive correlation between the urinary free cortisol excretion and traits such as anxiety and paranoid thoughts, meaning that as the concentration of urinary free cortisol increased so might the tendencies for these behaviors. The associations observed in the controls were in line with previously established correlations between cortisol production and stress-related behaviors.
General Observations and Conclusions
Parents of patients with CAH were more likely to be excluded from participating in the study than parents of children with other endocrine conditions. Exclusion was based on having a medical or psychiatric condition that would interfere with the testing. In the subjects studied, carriers of 21-OH deficiency had significantly lower 24-hour urinary free cortisol levels and had significantly higher ACTH and 17-hydroxyprogesterone response after CRH stimulation. These findings suggest that in carriers, the hypothalamus is mildly compensating for the low levels of cortisol by producing more CRH and ACTH. Such a finding is of interest as previous studies have shown that an overactive hypothalamus, excessive secretion of CRH, and low cortisol production have behavioral effects. Oversecretion of CRH has been documented in states of anxiety and depression. Chronic low cortisol production has been associated with several disorders, ranging from depression, chronic fatigue syndrome, fibromyalgia (persistent pain), and the postpartum period. Therefore our findings suggest that carriers of 21-OH deficiency may be genetically vulnerable or predisposed to the development of emotional or anxiety disorders upon exposure to adverse environmental factors.
Figure 1: Baseline and CRH-stimulated responses of ACTH (Panel A), cortisol (Panel B) and 17-hydroxyprogesterone (Panel C) in carriers of 21-hydroxylase deficiency (dark circles) and healthy controls subjects (open circles). Panel D shows mean 24-hour urinary free cortisol excretion in carriers of 21-hydroxylase deficiency and healthy control subjects. Carriers had significantly higher CRH-stimulated ACTH (P=0.04) and 17-hydroxyprogesterone (P<0.001) concentrations and lower mean 24-hour urinary free cortisol excretion (P=0.03) than healthy control subjects (from Charmandari E, et al. J Clin Endocrinol Metab 89:2228-2236, 2004; with permission)
Panel A (above)
Panel B (above)
Panel C (above)
Panel D (above)