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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 5 2228-2236
Copyright © 2004 by The Endocrine Society

Endocrinologic and Psychologic Evaluation of 21-Hydroxylase Deficiency Carriers and Matched Normal Subjects: Evidence for Physical and/or Psychologic Vulnerability to Stress

Evangelia Charmandari, Deborah P. Merke, Paulo J. Negro, Margaret F. Keil, Pedro E. Martinez, Adam Haim, Philip W. Gold and George P. Chrousos

Pediatric and Reproductive Endocrinology Branch (E.C., D.P.M., M.F.K., G.P.C.), National Institute of Child Health and Human Development, The Warren Grant Magnuson Clinical Center (D.P.M.), and Clinical Neuroendocrinology Branch (P.J.N., P.E.M., A.H., P.W.G.), National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Evangelia Charmandari, Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, Room 9D42, Bethesda, Maryland 20892-1583.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Carriers of congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency demonstrate increased secretion of cortisol precursors after ACTH stimulation, suggestive of impaired cortisol production and compensatory increases in hypothalamic CRH secretion. Because both cortisol and CRH have behavioral effects, and hypothalamic CRH hypersecretion has been associated with chronic states of anxiety and depression, we performed endocrine and psychologic studies in consecutively admitted parents of patients with classic congenital adrenal hyperplasia due to 21-OH deficiency and parents of children with other chronic endocrine disorders. The number of excluded carriers because of pathologic reasons was higher than that of controls (P = 0.05). Carriers of 21-OH deficiency had a lower mean 24-h urinary free cortisol excretion (26.4 ± 3.4 vs. 42.7 ± 6.4 µg/d, P = 0.03) and higher peak ACTH (75.7 ± 8.1 vs. 54.2 ± 5.9 pg/ml, P = 0.04) and 17-hydroxyprogesterone (224.2 ± 28.1 vs. 107.1 ± 12.5 ng/dl, P < 0.001) concentrations post CRH stimulation than control subjects. Cortisol and androstenedione responses were similar in the two groups. Psychometric assessment performed by administering the State-Anxiety Inventory, Beck Depression Inventory, Profile of Mood States, Symptom Checklist-90R, and Temperament and Character Inventory revealed no differences between the two subject groups. Interestingly, a stepwise multiple linear regression model analysis in each population sample revealed that in carriers of 21-OH deficiency but not in the control subjects, a lower mean 24-h urinary free cortisol excretion and a higher ACTH response to ovine CRH stimulation predicted predisposition to obsessive-compulsive behavior, novelty seeking, reward dependence, and harm avoidance. We conclude that carriers of 21-OH deficiency appear to have mild hypocortisolism and compensatory changes of CRH secretion secondary to lower cortisol concentrations. These changes might predict mild predisposition of these subjects to physical and psychologic pathology, suggesting that larger studies are necessary.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONGENITAL ADRENAL HYPERPLASIA (CAH) due to 21-hydroxylase (21-OH) deficiency is an autosomal recessive condition in which deletions or mutations of the cytochrome P450 21-OH gene result in decreased synthesis of glucocorticoids and/or mineralocorticoids. Decreased glucocorticoid feedback inhibition at the hypothalamic and anterior pituitary levels leads to increased secretion of CRH and ACTH, respectively, adrenocortical hyperplasia, and excessive production of adrenal androgens and steroid precursors before the enzymatic defect (1, 2, 3). The clinical spectrum of the disease ranges from most severe to mild forms, depending on the degree of the 21-OH activity defect. Accordingly, three main clinical phenotypes of CAH have been described: classic salt wasting, classic simple virilizing, and nonclassic or late-onset CAH (1, 2, 3, 4).

The prevalence of classic 21-OH deficiency is high, affecting about 1 in 10,000 individuals (1, 4), whereas heterozygocity for this disorder varies considerably, ranging from 1 in 20 to 1 in 60 in large populations and ethnic groups (5, 6). Following ACTH stimulation, carriers of 21-OH deficiency display increased secretion of cortisol precursors, including 17-hydroxyprogesterone (17-OHP), and lower concentrations of 11-deoxycorticosterone and aldosterone, compared with normal subjects (7, 8, 9, 10). In 50–80% of 21-OH deficiency carriers, 17-OHP responses to ACTH stimulation fall above the 95th percentile for the control population (7, 8, 9, 10), indicating that the majority of these subjects may have mild impairment in cortisol biosynthesis and, consequently, compensatory increases of hypothalamic CRH secretion.

CRH, a 41-amino acid peptide initially described as the principal hypothalamic hormone that regulates the hypothalamic-pituitary-adrenal (HPA) axis, is also a central coordinator of the endocrine, autonomic, immune, and behavioral responses to stress (11, 12, 13). CRH neurons are heterogeneously distributed throughout the central nervous system (CNS): 1) in the medial and lateral parvocellular region of the paraventricular nucleus, in which they form the central constituent of the neuroendocrine and autonomic response to stress; 2) in cortical regions, in which they may influence the behavioral responses to stress as well as the cognitive appraisal of stressful situations; 3) in the central nucleus of the amygdala, a limbic brain region involved in the processing of fear, in which they play a role in the modulation of affective stress responses; and 4) in brain stem nuclei, in which they modulate monoaminergic neurotransmitter systems involved in the pathophysiology of mood and anxiety disorders. An equally widespread distribution of at least two types of CRH receptors in the terminal fields of CRH neurons has also been described (14).

The stress response is largely characterized by activation of the HPA axis and locus ceruleus (LC)-norepinephrine (NE)/sympathetic nervous systems (11, 12, 13, 14, 15, 16, 17). Circulating glucocorticoids control the activity of the HPA axis by exerting negative-feedback effects at suprahypothalamic, hypothalamic, and anterior pituitary levels. However, a positive feed-forward cascade also exists between glucocorticoids and extrahypothalamic/amygdalar CRH, in which stress-induced increases in glucocorticoid secretion may further enhance CRH neuronal activity in circuits involved in behavioral responses to stress (13, 18, 19, 20).

Both hypothalamic and extrahypothalamic CRH neurons may play a substantial role in the development of and/or vulnerability to stress and affective disorders (17). When administered centrally, CRH produces many physiologic and behavioral changes reminiscent of acute stress, anxiety, and depression. CRH has been implicated in the pathogenesis of a variety of anxiety/affective disorders, mainly through CRH neurocircuits connecting the amygdala and the LC-NE/sympathetic nervous systems, whereas stress in early life results in persistent central CRH hyperactivity and increased stress reactivity in childhood and adulthood (21). Therefore, genetic predisposition coupled with stress in critical phases of development may result in a phenotype that is neurobiologically vulnerable to stress and may lower an individual’s threshold for developing depressive and anxiety disorders on subsequent exposure to stress.

The aim of the present study was to determine the endocrine and psychologic profile of obligate heterozygote parents of children with 21-OH deficiency and investigate the association between their adrenocortical responses to CRH stimulation and various psychometric parameters determined at psychologic evaluation.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Thirty-four consecutive parents of children with classic CAH and, hence, obligate 21-OH deficiency carriers, and 23 normal subjects were interviewed for entry into the study. Of those, 18 carriers of 21-OH deficiency (six males and 12 females; median age 40.6 yr, age range 30.2–50.1 yr) and 16 normal subjects (five males and 11 females; median age 43.4 yr, age range 32.2–52.1 yr) fulfilled the criteria for inclusion and were studied prospectively. The carrier state of 21-OH deficiency was confirmed by genotype in eight of the 18 obligate carriers of 21-OH deficiency.

All normal subjects were parents of children with a chronic endocrine disorder, such as Turner’s syndrome (n = 13) or Cushing’s disease (n = 2); one normal subject was an adoptive parent to a child with CAH.

Sixteen obligate carriers and seven control subjects were excluded from the study because of reasons summarized in Table 1Go. No subject included in the study had family history of mental illness or evidence of hepatic or renal disease, and none was receiving psychotropic medications or medications known to influence HPA axis activity or cortisol binding globulin (CBG) concentrations, or to induce hepatic enzymes. The clinical characteristics of all subjects recruited to participate in the study are summarized in Table 1Go.


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  		TABLE 1. Populations screened and clinical characteristics and endocrine parameters determined in the 34 subjects included in the study

 
The study was approved by the Institutional Review Board at the National Institute of Child Health and Human Development, NIH. Written informed consent was obtained in all cases.

Methods

All subjects were admitted to the NIH Clinical Center 1 d before the study, and standard anthropometric, hematologic, and biochemical measurements were obtained. An indwelling venous catheter was inserted 2 h before sampling to allow a period of adaptation. All subjects were fasting for 12 h before blood samples were collected.

On the first and second days of the study, 24-h urine specimens were collected for measurement of urinary free cortisol. On the third day, ovine (o) CRH was given iv (1 µg/kg) at 0800 h and blood samples for measurement of ACTH, cortisol, 17-OHP, and androstenedione concentrations were collected at –5, 0, 15, 30, and 45 min after stimulation. An additional blood sample for measurement of CBG concentration was drawn at 0800 h, before the administration of oCRH. Samples were centrifuged and separated immediately after collection and were stored at –80 C until assayed.

Psychometric assessment

The following instruments were administered to all subjects at baseline:

State-Anxiety Inventory (STAI). The STAI consists of 20 items to assess state anxiety (STAI 1) and another 20 items to assess trait anxiety (STAI 2). State anxiety is defined as an unpleasant emotional arousal in face of threatening demands or dangers. A cognitive appraisal of threat is a prerequisite for the experience of this emotion. Trait anxiety, on the other hand, reflects the existence of stable individual differences in the tendency to respond with state anxiety in the anticipation of threatening situations (22).

Beck Depression Inventory. This inventory is a 21-item scale that assesses depressive mood and cognition (23).

Profile of Mood States (POMS). This is a 65-item instrument composed of adjectives and a five-point Likert scale ranging from 0 (not at all) to 4 (extremely) assigned to each word put forward as a tool for description of mood. The questionnaire identifies six mood dimensions, including tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and confusion-bewilderment (24).

Symptom Checklist-90R. This is a 90-item multidimensional rating scale designed to measure current symptomatology and distress. Subjects indicated the amount of disturbance a particular item produced during the past week on a Likert scale ranging from 0 (not at all) to 4 (extremely). An average of all items (i.e. Global Severity Index) is used as a global measure of distress. In addition, there are nine symptom clusters (comprised of 10 items each): somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. Scores for each are derived from the average of each symptom cluster’s items (25).

Temperament and Character Inventory. This is a 240-item questionnaire to assess personality style. The inventory describes normal personality by four putatively inborn temperamental dimensions (novelty seeking, harm avoidance, reward dependence, and persistence) and three character dimensions (self-directedness, cooperativeness, and self-transcendence) (26).

Assays

Cortisol. Plasma cortisol concentrations were determined using a RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA) with a sensitivity of 1 µg/dl. The intraassay coefficients of variation (CVs) were 6.7, 6.2, and 7.3% at 6.6, 14.6, and 33.5 µg/dl, respectively. The interassay CVs were 9.0, 10.0, and 10.0% at 6.6, 14.6, and 33.0 µg/dl, respectively. Urinary free cortisol was determined in an aliquot of a 24-h specimen using a RIA (GammaCoat cortisol 125I RIA kit, DiaSorin Inc., Stillwater, MN) with a sensitivity of 0.21 µg/dl. The intraassay CVs were 9.1 and 4.3% at 1.2 and 5.2 µg/dl, respectively. The interassay CVs were 10.3 and 8.6% at 1.2 and 5.2 µg/dl, respectively.

CBG. CBG was measured using a RIA (RADIM, Covance Laboratories, Vienna, VA) with a sensitivity of 6.0 µg/ml. The interassay and intraassay CVs were 3.6 and 7.5%, respectively, at 43 µg/ml.

ACTH. ACTH concentrations were determined by an immunoradiometric assay (ACTH IRMA, Nichols Institute Diagnostics) with a sensitivity of 1 pg/ml. The within-assay variations were 3.0 and 3.2% at concentrations of 35 and 366 pg/ml, respectively. The between-assay variations were 7.8 and 6.8% at 236 and 358 pg/ml, respectively.

17-OHP. 17-OHP was measured by a radioimmunometric assay after extraction from plasma and purification by column chromatography (Covance Laboratories). The sensitivity of the assay was 5.0 ng/dl. The intraassay CVs were 14, 9.4, and 13% at 63, 188, and 303 ng/dl, respectively. The interassay CVs were 8.5, 8.9, and 7.4% at serum concentrations of 74, 204, and 346 ng/dl, respectively.

Androstenedione. Androstenedione was measured using a RIA (Diagnostic Systems Laboratories, Webster, TX) with a sensitivity of 3 ng/dl. The intraassay CVs were 5.6, 4.3, and 2.8% at 71, 232, and 722 ng/dl, respectively. The interassay CVs were 9.8, 6.0, and 7.0% at 61, 201, and 617 ng/dl, respectively.

Statistical analyses

Nonnormally distributed data were logarithmically transformed before statistical analysis. The total area under the plasma concentration curve of a given hormone vs. time (AUC) was estimated using the trapezoid method. This is a numerical integration method used to approximate the AUC. The time axis is divided into segments or periods between each time point, and the area above each segment is calculated by multiplication of the average of the hormone concentrations value and the time period. The areas of all trapezoids are then added to obtain the total AUC.

Comparisons between the proportions of the subjects excluded from each experimental group were performed using the {chi}2 test. Comparisons between the two groups of subjects were performed using the Student t test. The relation between endocrine and psychometric parameters was investigated by calculation of Pearson’s correlation coefficient. Stepwise multiple linear regression analysis was used to investigate independent predictors of hormonal and psychometric parameters in both groups of subjects. Hormonal independent variables tested included peak concentrations and total AUC of ACTH, cortisol, and 17-OHP post-oCRH stimulation. Psychometric variables tested included all those listed above. Values are expressed as mean ± SEM, unless otherwise specified.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Comparison between the proportions of subjects excluded from each group because of associated pathologic medical conditions (16 of 34 carriers of 21-OH deficiency and five of 23 normal subjects) revealed a greater rate of pathology in the carriers of 21-OH deficiency than the controls (P = 0.05) (Table 1Go). There was no difference in the proportion of subjects suffering from depression between the two groups (seven of 34 carriers and four of 23 normal subjects, P = 0.6). Granted that the carrier state in the general population ranges between 1 and 5%, the above trends might be important, and larger studies on 21-OH deficiency carriers should be performed to replicate or refute these findings.

The results of the endocrine and psychometric evaluation of subjects included in the study are shown in Fig. 1Go and Tables 1Go and 2Go.



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  		FIG. 1. Basal and oCRH-stimulated responses of ACTH (A), cortisol (B), 17-OHP (C), and androstenedione (D) in carriers of 21-OH deficiency (dark circles) and normal subjects (open circles). E, Mean basal 24-h UFC excretion in carriers of 21-OH deficiency and normal subjects. Carriers of 21-OH deficiency had significantly higher oCRH-stimulated ACTH (P = 0.04) and 17-OHP (P < 0.001) concentrations and lower mean 24-h UFC excretion (P = 0.03) than normal subjects. The asterisks indicate significant differences between the two groups. Inserted panels indicate the corresponding AUCs in each group.

 

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  		TABLE 2. Psychometric parameters determined in the 34 subjects included in the study

 
Endocrine parameters

Carriers of 21-OH deficiency had significantly lower mean 24-h urinary free cortisol (UFC) excretion (P = 0.03) and higher mean and peak ACTH and 17-OHP concentrations post oCRH stimulation (P < 0.05) than their normal counterparts. There was no difference in plasma cortisol and androstenedione concentrations post oCRH stimulation between the two groups (Table 1Go and Fig. 1Go).

Psychometric parameters

Carriers of 21-OH deficiency had higher total score in POMS than normal subjects; however, this difference did not reach statistical significance. There was no significant difference in any other psychometric parameter studied between the two groups (Table 2Go). Psychometric assessment did not indicate underlying pathology in any of the subjects studied.

Pearson’s correlation

In carriers of 21-OH deficiency, there was a negative correlation between mean 24 h UFC excretion and obsessive-compulsive behavior (r = –0.690, P = 0.013), novelty seeking (r = –0.613, P = 0.015), and reward dependence (r = –0.624, P = 0.013). Peak 17-OHP concentrations correlated negatively with anxiety (r = –0.634, P = 0.02) and hostility (r = –0.871, P < 0.001).

In normal subjects, there was a positive correlation between mean 24-h UFC excretion and anxiety (r = 0.668, P = 0.049), confusion-bewilderment (r = 0.750, P = 0.02), total mood score (POMS) (r = 0.923, P = 0.009), obsessive-compulsive behavior (r = 0.677, P = 0.022), phobic anxiety (r = 0.952, P = 0.013), and paranoid ideation (r = 0.833, P = 0.039). Also, there was a positive correlation between peak ACTH concentrations post oCRH stimulation and vigor-activity (r = 0.535, P = 0.049). Total AUC of ACTH post oCRH stimulation was correlated positively with vigor-activity (r = 0.585, P = 0.036) and negatively with fatigue-inertia (r = –0.640, P = 0.025) and confusion-bewilderment (r = –0.656, P = 0.028).

Stepwise multiple linear regression

In carriers of 21-OH deficiency, obsessive-compulsive behavior, novelty seeking, and reward dependence were independently related to mean 24-h UFC excretion. Harm avoidance was best predicted by peak ACTH concentrations post oCRH stimulation. There was a negative correlation between stimulated 17-OHP concentrations and trait anxiety score (STAI 2), interpersonal sensitivity, anxiety, and hostility (Table 3Go).


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  		TABLE 3. Stepwise multiple linear regression model for independent predictors of psychometric parameters in 21-hydroxylase deficiency carriers

 
In normal subjects, individual mood dimensions in the profile of mood states, including depression-dejection, vigor-activity, and fatigue-inertia were best predicted by the AUC of cortisol after oCRH stimulation (Table 4Go). Tension anxiety, phobic anxiety, and paranoid ideation were independently related to mean 24-h UFC excretion (Table 4Go).


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  		TABLE 4. Stepwise multiple linear regression model for independent predictors of psychometric parameters in normal subjects

 
It should be noted that a large number of dependent variables were examined and marginally significant P values should be treated with caution.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Carriers of 21-OH deficiency had significantly lower mean 24-h UFC excretion, higher ACTH and 17-OHP responses to oCRH stimulation, an increased incidence of physical and psychiatric pathology, and some deterioration in their profile of mood states, compared with their matched controls. Like CAH, Turner’s syndrome is a chronic endocrine disorder with potential severe complications, such as coarctation of the aorta, aortic root dilatation and dissection, pulmonary hypertension, and heart failure. Therefore, parents of patients with Turner’s syndrome were used as controls in terms of the psychologic impact secondary to the stress of raising a child with a chronic illness.

Chronic mild hypocortisolism has been associated with several human disorders, such as fibromyalgia and chronic fatigue syndrome, as well as atypical depression and the postpartum period, all states associated with increased autoimmune and psychiatric pathology (11, 12, 13, 15). The decreased mean 24-h UFC excretion and the increased stimulated ACTH and 17-OHP concentrations in the carriers were associated with increased obsessive-compulsive behavior, interpersonal sensitivity, anxiety, hostility, novelty seeking, harm avoidance, and reward dependence. These findings most likely reflect mild compensatory changes in hypothalamic CRH secretion secondary to the lower cortisol concentrations in 21-OH deficiency carriers and may predict predisposition of these subjects to affective and anxiety disorders. On the other hand, the positive correlations of 24-h UFC excretion with tension anxiety, phobic anxiety, and paranoid ideation in the control group of parents may reflect established correlations between HPA axis activity and stress-related behaviors (12).

Central hypothalamic and amygdalar CRH hypersecretion has been documented in several affective and anxiety states. In melancholic depression, patients demonstrate elevated cerebrospinal fluid CRH concentrations, increased hypothalamic CRH and CRH mRNA expression, defective suppression of ACTH and cortisol by dexamethasone, and reduced ACTH but normal cortisol responses to exogenous CRH stimulation (13, 18, 21). In obsessive-compulsive disorder, patients have increased cerebrospinal fluid CRH concentrations, which normalize on clinical recovery (27, 28). In generalized anxiety disorder or obsessive-compulsive disorder, there is increased HPA axis activity and defective suppression by dexamethasone (29), whereas in panic disorder, the initially increased but later blunted ACTH responses to CRH stimulation indicate that an initial CRH sensitization may evolve into adenohypophyseal CRH receptor down-regulation on long-term CRH hypersecretion (30).

Animal studies provide additional evidence for a central role of CRH in coordinating the stress response and participating in the pathogenesis of affective and anxiety states (12, 13). Direct CNS administration of CRH results in physiologic changes that closely parallel manifestations of stress as well as behavioral changes that resemble symptoms of anxiety and depression (11, 12, 13, 14, 15, 16, 17, 18, 31, 32). Transgenic mice overexpressing CRH or lacking CRH type 1 receptors demonstrate increased or decreased anxiety, respectively. The behavioral effects of CRH can be blocked by central administration of peptidic CRH receptor antagonists or a CRH antisense oligodeoxynucleotide, further underscoring the importance of endogenous CRH in mediating anxiety and depression (19, 31, 33, 34).

Extrahypothalamic CRH neuronal systems connecting the amygdala with the LC-NE/sympathetic nervous systems represent a major neurotransmitter circuit that is activated in anxiety states (21). Both acute and chronic stress increase CRH concentrations in the amygdala and the LC-NE area. Microinjection of CRH directly into the amygdala or the LC and the parabrachial nucleus suppresses exploratory behavior in a novel environment and facilitates fear conditioning and conflict behavior, whereas nonpeptidic CRH receptor antagonists administered systemically, or peptidic CRH receptor antagonists administered locally into the amygdala or LC, attenuate shock-induced freezing behavior. Finally, lesions of the amygdala abolish the CRH-induced potentiation of startle responses and conditioned emotional responses (19, 21, 35, 36, 37).

Multiple sites of interaction exist between the various components of the stress system (13) (Fig. 2AGo). In normal subjects and in the absence of stressful stimuli, the stress system is in a dynamic state of multidirectional interactions among stress mediators. Data in experimental animals suggest that under ordinary circumstances: 1) the prefrontal cortex, an important component of the mesocortical dopaminergic system, inhibits the amygdala, HPA axis, and LC-NE system; 2) an activated amygdala stimulates the mesocorticolimbic system, HPA axis, and LC-NE system; 3) the LC-NE system activates the amygdala, HPA axis, and mesocorticolimbic system; and 4) the HPA axis activates the LC-NE system and amygdala. The amygdala, LC-NE, and CRH systems are all excitatory to one another so that an increase in the activation of one component could set off a reverberative sequence of further activations unless overtaken by inhibitory stimuli (13) (Fig. 2AGo).



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  		FIG. 2. A, Schematic representation of the interrelation of the stress system and other brain circuitries in normal subjects. We hypothesize that carriers of 21-OH deficiency have readjustments consistent with low cortisol and high paraventricular nucleus CRH, altering the equilibrium with the rest of the stress system in the brain stem, i.e. the LC-NE, hippocampus, mesolimbic (ML) and mesocortical (MC) systems. Solid lines represent activation and dashed lines indicate inhibition. AVP, Arginine-vasopressin; PFC, prefrontal cortex; PVN, paraventricular nucleus (adapted from Chrousos GP, Gold PW. The inhibited child syndrome. In: Schmidt LA, Schulkin J, eds. Extreme fear, shyness and social phobia: origins, biological mechanisms and clinical outcomes. New York: Oxford University Press; 1999:193–200). B, Schematic representation of the interrelation between CRH or cortisol concentrations and sense of well-being or performance. Normal CRH/cortisol secretion is associated with optimum sense of well-being, whereas both CRH and cortisol hypo- or hypersecretion lead to compromised sense of well-being and/or performance. Whereas most normal subjects fall within the optimum range, we hypothesize that carriers of 21-OH deficiency have shifts toward the right or left of the optimum range because of high CRH and low cortisol concentrations, respectively. These shifts may explain the correlation between altered HPA axis activity and certain psychologic parameters.

 
In carriers of 21-OH deficiency, the lower basal 24-h UFC excretion indicates mild elevations of hypothalamic CRH secretion, whereas the increased ACTH and 17-OHP responses to CRH stimulation most likely reflect chronic hypothalamic hyperactivity and increased/unopposed CRH secretion secondary to the impaired cortisol biosynthesis. This hyperactivity at baseline and/or under stress might lead to the development of affective disorders. Thus, carrier status of 21-OH deficiency may be conceptualized as a long-standing, mildly intensified stress response that causes a shift in the equilibrium and results in activation of the hypothalamic stress system along with resultant concurrent changes in the brain stem LC-NE system and other functionally related systems influencing affect and behavior, including the amygdala and mesocortical and mesolimbic systems (Fig. 2Go, A and B).

The long-standing changes in cortisol and CRH secretion in carriers of 21-OH deficiency may have important clinical implications for their psychologic profile and overall vulnerability to stress. Stress early in development may result in persistently increased activity of CNS CRH systems and sensitization of the HPA axis and LC-NE systems to even mild stress in adulthood, thus forming the basis for the development of mood and anxiety disorders. In rats, maternal separation in the immediate postnatal period results in increased HPA axis and LC-NE system activity, increased hypothalamic and extrahypothalamic CRH concentrations and CRH mRNA expression, and increased anxiety-like behaviors (21, 38, 39, 40, 41, 42). Similar findings have been documented in young adult nonhuman primates who have been maternally deprived during infancy (43). In humans, subjects of childhood abuse demonstrate chronic, persistent, increased ACTH responses to stress, which are positively correlated with the degree of childhood abuse (44, 45). Therefore, stress early in development, in association with persistent hyperactivity and/or sensitization of the CNS/CRH systems, may alter the set point of the stress system response, rendering these individuals particularly vulnerable to adverse experiences and increasing their risk for stress-related diseases in adulthood (46). This vulnerability may result in relatively high CRH secretion on subsequent stress exposure, which may eventually lead to affective and anxiety disorders because of the behavioral effects of CRH and NE at extrahypothalamic sites. A lack of proper negative feedback inhibition at the hypothalamic and adenohypophyseal levels by cortisol might further modulate CRH release and potentiate the above effects (21).

We conclude that carriers of 21-OH deficiency have mild chronic hypocortisolism and increased ACTH responses to oCRH stimulation. In addition, albeit in a small pilot study, we noted some deterioration in mood, compared with normal subjects. These findings may reflect chronic mild hypothalamic CRH secretion changes, which may render these subjects genetically vulnerable and, on further exposure to adverse environmental factors, might predispose them to the development of physical, affective, and/or anxiety disorders.


   Footnotes
 
D.P.M. is a Commissioned Officer in the U.S. Public Health Service.

Abbreviations: AUC, Total area under the plasma concentration curve of a given hormone vs. time; CAH, congenital adrenal hyperplasia; CBG, cortisol binding globulin; CNS, central nervous system; CV, coefficient of variation; LC, locus ceruleus; NE, norepinephrine; o, ovine; 21-OH, 21-hydroxylase; 17-OHP, 17-hydroxyprogesterone; POMS, Profile of Mood States; STAI, State-Anxiety Inventory; UFC, urinary free cortisol.

Received July 31, 2003.

Accepted February 17, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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