Pii: s0006-3223(99)00081-5

Late-Onset Congenital Adrenal Hyperplasia:A Treatable Cause of Anxiety Alan R. Jacobs, Phyllis B. Edelheit, Anton E. Coleman, and Andrew G. Herzog Background: Some intermediaries of cortisol synthesis,
zymes essential for cortisol biosynthesis (Eldar-Geva et al especially the sulfated ester of dehydroepiandrosterone 1990; Miller 1991). CAH is most commonly due to an (DHEAS), are picrotoxin-like antagonists of the -ami- enzyme deficiency of 21-hydroxylase, 11-␤-hydroxylase nobutyric acid A (GABA-A) receptor and exert potent or 3-␤-oxidoreductase, alone or in combination (Eldar- anxiogenic effects. We report 5 men and 7 women with Geva et al 1990; Miller 1991). In women, CAH can cause refractory anxiety disorders, who had late-onset congen- hirsutism, menstrual disorders, and infertility (Eldar-Geva ital adrenal hyperplasia (CAH), and in whom interactionsbetween neuroactive steroids and anomalous brain sub- et al 1990; Miller 1991). In men, distinguishing physical strates may have participated in the pathophysiology and features are generally absent. While the coexistence of mood disorder and CAH has been described (Feldman et Methods: Twelve patients with refractory anxiety disor-
al 1987), a possible role for CAH in anxiety disorders has ders as defined by DSM-IV had elevated DHEAS and specific enzyme deficiencies diagnostic of CAH. All were There is reason to consider a pathophysiologic role for treated with adrenal suppressive therapy using ketocon- CAH in anxiety disorders. CAH can cause the accumula- azole or low (physiologic) dose glucocorticoids. Anxiety tion of intermediaries in the adrenal steroid hormone was rated by the Tension Scale of the Profile of Mood synthetic pathways. Some of these compounds, especially States (POMS Tension) questionnaire before and during dehydroepiandrosterone sulfate (DHEAS) and preg- nenolone sulfate, are neurosteroids that have potent activ- Results: Reduction of DHEAS was associated with lower
ity as antagonists at the ␥-aminobutyric acid-A (GABA-A) anxiety scores in all twelve cases. POMS Tension scores receptor in the brain. They can exert potent anxiogenic, decreased by 55%. Hormonal treatment, which failed to proconvulsant, and convulsant effects (Deutsch et al 1992; Paul and Purdy 1992). Excitatory neurosteroids may be Conclusions: These findings suggest that late onset CAH
more apt to cause emotional disorders in individuals with can contribute to anxiety disorders and that adrenal anomalous brain substrates than in those who have not suppressive therapy or inhibition of steroidogenesis with inherited or acquired any degree of cerebral dysfunction ketoconazole may be efficacious as adjuvant therapy. (Brooks-Kayal et al 1998a; 1998b; Geschwind et al 1985; Biol Psychiatry 1999;46:856 – 859 1999 Society of Herzog 1989; Schmidt et al 1998). We report 5 men and 7 women with refractory anxiety disorders who were dem-onstrated to have CAH and whose anxiety decreased Key Words: Anxiety, dehydroepiandrosterone sulfate,
adrenal, behavior, hormones
Methods and Materials
The men and women ranged in age from 16 to 55 years and were Late-onset congenital adrenal hyperplasia (CAH) is an diagnosedbypsychiatristsorbehavioralneurologiststohavean autosomal recessive adrenocortical disorder that oc- anxiety disorder as defined by DSM-IV criteria. Anxiety, in all curs in approximately 1% of the general population and is cases, was considered refractory to psychotropic medications characterized by partial deficiency of steroidogenic en- (protracted trials of benzodiazepines, antidepressants, moodstabilizers, and/or major tranquilizers) because of inadequateefficacy or intolerable side effects. The anxiety disorders in- From the Harvard Neuroendocrine Unit, Beth Israel Deaconess Medical Center, 330 cluded generalized anxiety, panic disorder, phobias, and obses- Brookline Avenue, Boston, MA (AEC, AGH); the Neuroendocrine Unit,Department of Neurology, The New York Hospital/Cornell University Medical sive-compulsive disorder. Some also suffered from depressive or Center, New York, NY (ARJ); and the Division of Child and Adolescent bipolar forms of major mood disorder. Ten of the twelve had Psychiatry, Department of Psychiatry, Long Island Jewish Medical Center/Schneider Children’s Hospital/Hillside Hospital, New Hyde Park, NY (PBE).
some evidence, by history, examination, or laboratory (neuro- Address reprint requests to Andrew G. Herzog, MD, MSc, Director, Harvard psychologic, electroencephalographic, or brain imaging) investi- Neuroendocrine Unit, Beth Israel Deaconess Medical Center, 330 Brookline gations, of forebrain anomaly. All patients were found to have Received November 20, 1998; accepted March 11, 1999; accepted March 16, 1999.
elevated levels of DHEAS and subsequently were shown to have specific enzyme deficiencies diagnostic of CAH (Eldar-Geva et Table 2. Adrenal Hormonal Data and Associated POMS al 1990). Table 1 provides details of demographic, historical, Tension Scores in Patient 4 before and during Low and High clinical, and laboratory data for the 12 patients.
Adrenal suppressive therapy was added to existing treatment regimens in all 12 cases. Treatment duration at the time of thisreport ranged between 3 to 16 months. Ketoconazole was considered the therapy of choice because low doses selectively inhibit C17,20-lyase, the enzyme directly responsible for the conversion of 17-hydroxypregnenolone to dehydroepiandros- terone (Couch et al 1987; Holland et al 1985; Sonino 1987).
Glucocorticoid treatment was used for suppression when normal- ization of DHEAS could not be achieved with ketoconazole (patients 1, 7, and 12). Table 1 presents the specific regimens and Anxiety was rated by the Tension score of the Profile of Mood States (POMS) (McNair et al 1992) questionnaire. All 12 patients completed pre- and post-treatment POMS questionnaires. All attempts were made to keep constant the doses of any concom- itant psychoactive medications during the period of treatmentwith adrenal suppressive medication.
DHEAS, dehydroepiandrosterone sulfate; 17 OH Preg, 17-hydroxypreg- nenolone; E2, estradiol; DOC, deoxycorticosterone; 17 OH Prog, 17-hydroxypro-gesterone; Prog, progesterone; POMS, Tension score on Profile of Mood Scale Adrenal suppressive therapy was associated with a reduc- treatment, which was not accompanied by significant tion of anxiety in all 12 patients (p Ͻ .001, nonparamet- reduction of DHEAS, but did respond favorably to glu- ric sign test). The POMS tension scores were reduced by cocorticoids, which successfully lowered DHEAS levels.
an average of 55% (range: 31– 89%; p ϭ .003, Wilcoxon We speculate that alterations in the plasma concentra- signed rank test). In contrast, the POMS depression scores tions of anxiogenic and anxiolytic neuroactive adrenal showed inconsistent directional changes.
steroids may be important in the development and treat- A favorable clinical response was associated with nor- ment of anxiety disorders associated with CAH. Some malization or substantial reduction (greater than 10%) of major metabolites of progesterone and deoxycorticoste- DHEAS levels using ketoconazole in 8 patients. Patients rone act at the GABA-A receptor as positive allosteric 1, 7, 10, and 12 did not achieve substantial lowering of effectors with anxiolytic, sedative-hypnotic, and anticon- DHEAS levels on ketoconazole, but did so with glucocor- vulsant properties, while other intermediaries such as ticoids. Clinical improvement in these cases was associ- DHEAS and pregnenolone-sulfate have been shown to be potent GABA-A receptor antagonists with anxiogenic,proconvulsant, and convulsant properties (Deutsch et al Discussion
1992; Paul and Purdy 1992). Lowering DHEAS levels orraising progesterone metabolite levels, therefore, should We report 5 men and 7 women with refractory anxiety theoretically reduce anxiety disorders. This possibility is who were demonstrated to have CAH and responded supported by endocrine data in patient 4 (Table 2). At low favorably to reduction of serum DHEAS levels. There are doses, ketoconazole primarily inhibits 17,20-lyase, which reasons to consider that the response to therapy represents directly blocks the conversion of 17-hydroxypregnenolone more than a placebo effect. Anxiety in all of the patients in to dehydroepiandrosterone. In patient 4, this led to a the series was considered refractory to psychotropic med- decrease in all excitatory neuroactive hormones (DHEAS, ications because of inadequate efficacy or intolerable side 17-hydroxypregnenolone, and estradiol) and an increase in effects. The favorable responses were specific for anxiety all the inhibitory neurosteroids (deoxycorticosterone, 17- disorders, not mood disorders, and persisted for extended hydroxyprogesterone, and progesterone) (Deutsch et al durations (currently, 16 months in patient 11). Finally, 1992; Paul and Purdy 1992). These changes were associ- clinical improvement appeared to relate to endocrine ated with a marked reduction in anxiety (POMS decreased correction, as demonstrated by lowering of DHEAS.
41%). Higher dose ketoconazole begins to also inhibit Another possibility is that ketoconazole has sedative 11-␤-hydroxylase, which blocks cortisol synthesis, thus effects unrelated to its actions on steroidogenic enzymes.
increasing ACTH response and increasing global adrenal In patients 1, 7, 10, and 12, however, this is not the case steroid synthesis (Deutsch et al 1992; Paul and Purdy since these patients did not respond to ketoconazole 1992). This led to increases in all measured steroids, excitatory and inhibitory, and a moderate return of anxiety Deutsch SI, Mastropaolo J, Hitri A (1992): GABA-active ste- roids: Endogenous modulators of GABA-gated chloride ion The findings raise the possibility that the elevation of conductance. Clin Neuropharmacol 15(5):352–364.
excitatory neuroactive steroids, either in absolute terms or Eldar-Geva T, Hurwitz A, Vecsei P, Palti Z, Milwidsky A, Rosler A (1990): Secondary biosynthetic defects in women relative to inhibitory steroids, may be an important and with late-onset congenital adrenal hyperplasia. N Engl J Med treatable factor in the development of anxiety disorders in men and women with CAH, especially in the setting of Feldman SR, Krishnan KR, McPherson H, Meglin DE (1987): anomalous brain substrates. DHEAS may be a suitable Organic affective disorder in a patient with congenital adrenal screen for CAH in the majority of cases. Some individuals hyperplasia. Biol Psychiatry 22:767–770.
with CAH (e.g., those with 3-␤-oxidoreductase deficien- Geschwind N, Galaburda AM (1985): Cerebral lateralization.
cy), however, may have normal DHEAS levels and require screening of other intermediaries (e.g., androstenedione, Herzog AG (1989): Perimenopausal depression: Possible role of anomalous brain substrates. Brain Dysfunct 2:146 –154.
DHEA, or 17-hydroxyprogesterone). At present, the most Holland FJ, Fishman L, Bailey JD, Fazekas AT (1985): Keto- sensitive evaluation remains the 1,24-adrenocorticotropin conazole in the management of precocious puberty not stimulation test (Eldar-Geva et al 1990).
responsive to LHRH-analogue therapy. N Engl J Med 312:1023–1028.
McNair DM, Lorr M, Droppleman LF (1992): Profile of Mood States. San Diego, CA: Edits/Educational and Industrial Brooks-Kayal AR, Jin H, Price M, Dichter MA (1998a): Devel- opmental expression of GABA receptor subunit mRNAs in Miller WL (1991): Congenital adrenal hyperplasias. Endocrin individual hippocampal neurons in vitro and in vivo. J Neu- Metab Clin North Am 20:721–749.
Paul SM, Purdy RH (1992): Neuroactive steroids. FASEB J Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, Coulter DA (1998b): Selective changes in single cell GABA receptor Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow subunit expression and function in temporal lobe epilepsy.
DR (1998): Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome.
Couch RM, Muller J, Perry YS, Winter JS (1987): Kinetic analysis of inhibition of human adrenal steroidogenesis by Sonino N (1987): The use of ketoconazole as an inhibitor of ketoconazole. J Clin Endocrinol Metab 65:551–554.
steroid production. N Engl J Med 317:812– 818.

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