The excretion of urinary 11-deoxy- and 11-oxy- 17-hydroxy-corticosteroids in depressive patients during basal conditions and during the administration of methopyrapone

The excretion of urinary 11-deoxy- and 11-oxy- 17-hydroxy-corticosteroids in depressive patients during basal conditions and during the administration of methopyrapone

J. Psychosomatic Res., 1966, Vol. 9, pp. 363 to 374. Pergamon Press Ltd. Printed in Northern Ireland THE EXCRETION OF U R I N A R Y l l-DEOXY- A N D ...

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J. Psychosomatic Res., 1966, Vol. 9, pp. 363 to 374. Pergamon Press Ltd. Printed in Northern Ireland

THE EXCRETION OF U R I N A R Y l l-DEOXY- A N D l l-OXY17-HYDROXY-CORTICOSTEROIDS IN DEPRESSIVE PATIENTS D U R I N G BASAL CONDITIONS A N D D U R I N G THE ADMINISTRATION OF METHOPYRAPONE*'~ THEODOR JAKOBSON, ASSER S T E N B A C K ,

L.

STRANDSTR()M

and R. RIM6N

(Received 1 November 1965)

of adrenocortical hyperactivity such as an increased excretion of urinary corticoids [1] or elevated plasma 17-hydroxycorticoid levels [2, 3] has been reported during the course of depressive illness and more recently also an increased cortisol secretion rate which was found to be well correlated with the plasma cortisol levels has been demonstrated in this condition [4]. These signs of increased hormonal activity in depressive illness have usually been explained in terms of an increased production of ll-oxygenated steroids, such as cortisol, which are known to react to various forms of emotional stress, in particular to anxiety [5]. More recently it has been pointed out, however, that patients with similar clinical depression ratings can show different degrees of adrenocortical function and that the corticoid excretion of depressive patients is not always related to the amount of anxiety displayed by these individuals [6, 7]. In a previous study [8] urinary total 17-OHCS were determined by us in a group of depressive patients on admission to the hospital and following one month of treatment with antidepressive drugs and/or electroconvulsive therapy. An attempt was made at the same time to correlate the corticoid excretion values which were measured in these individuals with the depression and anxiety ratings obtained in the same subjects by means of Beck's Depression Inventory [9] and Taylor's Manifest Anxiety Scale [10]. The results of this study suggested that there are two types of depressive patients, one type with a high initial excretion of urinary 17-OHCS which in most cases decreased during the course of the treatment and one type with no demonstrable increase of urinary corticoid excretion. It was, however, not possible on the basis of the anxiety ratings to differentiate between depressive patients with a high degree of anxiety and subjects with no signs on anxiety because the scores of the anxiety tests corresponded to a high degree with scores obtained on the Depression Inventory and high anxiety ratings as well as high depression ratings were observed in most patients on admission to the hospital. The present study is concerned with the fractionation of urinary corticoids excreted by depressive patients into 11-deoxy- and 11-oxy-17-hydroxycorticoids by means of thin layer chromatography. The separation of urinary corticoids into these two fractions was carried out in depressive patients both under basal conditions and following the administration of methopyrapone. It will be demonstrated that there are in EVIDENCE

* From the Hesperia Hospital, Helsinki, Finland. t The study was aided by a grant from the Signe and Ane Gyllenberg Foundation. 363

364

T. JAKOBSON,A. STENB.~CK, L. STRANDSTROMand R. RIMON

d e p r e s s i v e subjects a l t e r a t i o n s f r o m n o r m a l in t h e e x c r e t i o n o f these t w o s t e r o i d f r a c t i o n s a n d t h a t t h e e x c r e t i o n o f b o t h g r o u p s o f steroid h o r m o n e d e r i v a t i v e s is c o r r e l a t e d w i t h the c h a n g e o f d e p r e s s i o n a n d a n x i e t y ratings o b s e r v e d d u r i n g the c o u r s e o f the study. MATERIAL AND METHODS The material consists of 16 depressed patients (9 females and 7 males) who were admitted to the Hesperia Hospital in Helsinki. This is a municipal neuropsychiatric hospital which is adjacent to a general hospital. Depression and anxiety ratings were obtained in the depressive patients on admission to the hospital and following approximately one month of treatment with antidepressive drugs or administration of electroconvulsive therapy. The test employed for the assessment of depression was Beck's Depression Inventory [9] and for the assessment of anxiety the Taylor Manifest Anxiety Scale [10] was used. Twenty-four-hour urine collections for the determination of adrenocortical steroids were carried out in every case prior to the initiation of treatment during four consecutive days. During the first two days the basal excretion of urinary steriods was determined. On the third day the patients received methopyrapone (Metopirone(R), Ciba) 750 mg every 4 hr for a total of 4-5 g daily. On the fourth day additional urine collections were carried out without administration of methopyrapone. The maximal response to the administration of methopyrapone in terms of an increase of the 11-deoxy-17-hydroxycorticoid fraction was in most cases seen on the fourth day and the steroid excretion on this day was therefore used in the evaluation of the methopyrapone test except in the few cases where the maximal response was seen already on the third day. Following treatment the urine collections were repeated in the same way and the same dose of methopyrapone was administered. An effort was made during the test periods to avoid all unnecessary medication which might interfere with the steroid determinations. Sixteen subjects (7 females and 9 males) who had been admitted to the neurological department of the hospital for the evaluation of headache, dizziness or minor neurological symptoms served as controls for the determinations of adrenocortical steroid excretion. Only subjects who did not show signs of any severe organic disease and who did not display any mental abnormalities were used as controls. The age distribution of the control group was similar to that of the study group. Following determination of the total daily output of 17-OHCS according to Appleby et al. [11] the corticoids were fractionated into 11-deoxy and 11-oxy compounds by means of thin layer chromatography. Theratio, ll-deoxy/ll-oxycompounds, which was first proposedby Hill[12]--the so-called 1l-oxygenation index--was determined for each urine specimen. This index gives the ratio between the urinary metabolites of cortisol precursors to those of cortisol. The used method is based on earlier works by Edwards et al. [13, 14], Few [15] and Pesonen et al. [16]. A volume of urine containing approximately 1"5 mg of 17-OHCS is acidified to pH 1.0 with hydrochloric acid, ammonium sulphate (50 g/100 ml) is added and the steroids are extracted according to Edwards et al. [13]. The crude residue is dissolved in acetate buffer at pH 4"1 and hydrolysed for 16 hr at +37°C with fl-glucuronidase (200 U/1 ml) and sulphatase (100 U/1 ml). The steroids are extracted with methylene dichloride which is washed with dilute sodium hydroxide and distilled water and evaporated to dryness. The residue is dissolved in a mixture of ethanol and distilled water (65:35). The 17-OHCS are separated from the 17-ketosteroids according to Appleby et al. [11]. The residue is further purified by partition with a mixture of 70 per cent methanol and light petroleum (1 : l). The methanol phase is evaporated to dryness. The 11-deoxyand 11-oxy compounds are separated by thin layer chromatography as described by Pesonen[17] with a mixture of ethyl acetate and cyclohexane (45:55). Prior to chromatography the extract is divided into two equal parts and both halves are applied separately to the glass plate. One half is developed and the second half is eluated for the quantitative dertermination of the steroid fractions. The Zimmermann reaction was used for all quantitative estimations. Etiocholanolone (3c~-hydroxy-5fl-androstan-17-one) and ll-hydroxyetiocholanolone (3c~,ll/3-dihydroxy-5fi-androstan-17-one) were used as chromatography reference standards. RESULTS The average excretion of urinary 1l-deoxy-17-hydroxycorticoids in depressive patients prior to treatment and following treatment with antidepressive drugs has been compared to the excretion of the same steroid fraction in normal control subjects (Table 1). The mean excretion of the ll-deoxycorticoids both in the untreated and treated depressive males was more pronounced than in the controls, the difference in both instances being statistically significant (p < 0.05). In the depressive females a similar difference (p < 0.05) was found to exist when the excretion of the same steroid fraction after one month of treatment was compared to the excretion values obtained in normal females, whereas the excretion of the 11-deoxy-corticoids was not found to be significantly increased in the untreated

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depressive females. The excretion of the 11-deoxy-steroids of the males was significantly higher (p < 0-01) than that of the females in all study groups. Table 1 shows also the excretion of urinary 11-oxy-17-hydroxycorticoidsin depressive patients and the excretion of the same steroid fraction in normal control subjects. The mean excretion of the l l oxygenated steroids in the depressive men was found to increase slightly following treatment, but the increase was not statistically significant. In the depressive females the excretion of this steroid fraction was the same as in the controls. Table 2 shows the average excretion of urinary ll-deoxy-17-hydroxycorticoids following the administration of methopyrapone to depressive patients prior to treatment and one month later as compared with the methopyrapone response in normal control subjects. When the methopyrapone response was determined as the difference between the amount of 11-deoxy-corticoidsexcreted following the administration of methopyrapone and the basal excretion of this steroid fraction prior to the administration of the blocking agent, the response in the untreated depressive males was found to be significantly (p < 0.05) less than in the control subjects or in the untreated depressive females. The total excretion of the 11-deoxy-corticoids following the administration of methopyrapone was only slightly less in the untreated depressive males than in the other groups, and the difference in response as determined by the increment in the excretion of the 11-deoxy-corticoidsmust therefore depend on the increase of the basal excretion of this steroid fraction observed in depressive men. The response to the administration of methopyrapone in the depressive females prior to treatment was found to be somewhat more pronounced than in the control subjects when measured either as the increment over the basal excretion or in terms of the total output of steroids excreted following the administration of the blocking agent. The difference was not statistically significant in either case. In Fig. 1 the changes observed in the Depression Inventory Scale and the Taylor Manifest Anxiety Scale respectively during the treatment of the depressive illness is plotted against the basal excretion of urinary 11-oxygenated corticoids measured in the same patients prior to the treatment of the depressive condition. The correlation between the decrease of both the depression and the anxiety ratings on the one hand and the steroid excretion on the other was found to be statistically very significant (o < 0.001). The correlation between the depression and anxiety scores and the excretion of urinary 11-deoxy17-hydroxycorticoids in depressive patients is shown in Fig. 2. A significant positive correlation (p < 0'01) was found only between the decrease of the Taylor Manifest Anxiety Score and the excretion of 11-deoxy-corticoids. The significance of the correlations between the changes of the depression and anxiety ratings following treatment of the depressive condition and the excretion of both urinary corticoid fractions have been calculated by means of the Spearman correlation coefficient both for the total group of depressive patients and separately for the depressive males and females, and are illustrated in Table 3. DISCUSSION U r i n a r y 1 7 - h y d r o x y c o r t i c o i d s were s e p a r a t e d by m e a n s o f thin layer c h r o m a t o g r a p h y into l l - d e o x y - 1 7 - h y d r o x y c o r t i c o i d s a n d into l 1-oxygenated c o m p o u n d s . The f o r m e r f r a c t i o n measures m a i n l y p r e c u r s o r s o f the biologically i m p o r t a n t cortisol, such as 11-deoxycortisol ( C o m p o u n d S) which can be f o r m e d in excessive a m o u n t s in some e n d o c r i n e d i s t u r b a n c e s which affect the n o r m a l steroid p r o d u c t i o n in the a d r e n a l cortex. Since this c o m p o u n d is also p r o d u c e d instead o f cortisol d u r i n g the artificial b l o c k i n g o f c o r t i s o l synthesis b y the a d m i n i s t r a t i o n o f m e t h o p y r a p o n e , the increased excretion o f 11-deoxy-17-hydroxycorticoids can u n d e r these circumstances be used in preference to the d e t e r m i n a t i o n o f u r i n a r y t o t a l 17-OHCS as a m e a s u r e o f the reactive increase o f the p i t u i t a r y A C T H secretion i n d u c e d b y the b l o c k i n g agent [18]. I n a d d i t i o n to 11-deoxycortisol o t h e r c o m p o u n d s with a similar configuration can be assayed as 11-deoxy-17-hydroxycorticoids. A significant increase was observed in the m e a n excretion o f 1 l - d e o x y - 1 7 - h y d r o x y corticoids o f depressive men. The relative increase o f this steroid fraction was p a r t i c u l a r l y p r o n o u n c e d in a few cases in which it seemed to persist, despite clinical i m p r o v e m e n t as m e a s u r e d b y the depression a n d anxiety ratings. In depressive w o m e n the m e a n excretion o f l l - d e o x y - h y d r o x y c o r t i c o i d s was less p r o n o u n c e d in the untreated patients than following t r e a t m e n t o f the depressive illness.

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F~G. 1. Correlation between the excretion of urinary ll-oxy-17-hydroxycorticoids in depressive patients and the change of (a) the Beck Depression Inventory and (b) the Taylor Manifest Anxiety Scale observed in the same patients following treatment of the depression. Although we are not aware of any other studies in which fractionation of urinary corticoids has been carried out by similar methods during the course of depressive illness, Ferguson et al. [19] separated the 17-oxosteroids excreted by a small group of depressive women into ll-deoxy- and l 1-oxygenated compounds. A low level of excretion of the former steroid fraction was found prior to treatment, followed by a rise to normal in clinical remission. Kurland [6] found a disproportionate elevation of urinary 17-ketogenic steroids (17-KGS) over that of the urinary total 17-hydroxycorticoids (17-OHCS) which were determined by a modified Silber-Porter procedure in 10 depressive men hospitalized at a U.S. Naval Hospital. Only the former group

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of steroids was excreted in greater absolute quantities than would be expected from a comparable group of normal control subjects. One of Kurlands explanations was that the disproportionate rise in 17-KGS may have been caused by the presence of a compound or compounds which results from a block in the metabolism of 17-OHCS and which is assayed as 17-KGS but not as a 17-OHCS (Porter-Silber chromogen). The results of the present investigation would seem to be in accordance with these observations. It could be similarly postulated that the increased excretion of 11-deoxycorticoids observed during the course of the present study results from an alteration of the metabolic pathway along which the synthesis of adrenal corticosteroids is

370

T. JAKOBSON,A. STENB,~CK, L. STRANDSTROMand R. RIMdN

proceeding under normal conditions. This alteration of normal steroid metabolism could be caused by a block of the final stages of cortisol synthesis similar to that which can be produced by the administration of blocking agents and which is also k n o w n to occur in congenital adrenal hyperplasia, and occasionally in other forms of adrenocortical hyperplasia [20, 21]. Other alterations of the normal metabolic pathways of steroid synthesis in the adrenal cortex have recently also been found to exist in association with various forms of adrenocortical hyperfunction [22]. TABLE 3 . - - S I G N I F I C A N C E OF CORRELATIONS BETWEEN THE CHANGE OF DEPRESSION AND ANXIETY RATINGS FOLLOWING TREATMENT OF DEPRESSIVE ILLNESS AND THE EXCRETION OF URINARY CORT1COSTEROID FRACTIONS

(a) Change of Beck Depression Inventory versus the excretion of urinary 11-oxy17-hydroxycorticoids (b) Change of Taylor Manifest Anxiety Scale versus the excretion of urinary ll-oxy17-hydroxycorticoids (c) Change of Beck Depression Inventory versus the excretion of urinary 11-deoxy17-hydroxycorticoids (d) Change of Taylor Manifest Anxiety Scale versus the excretion of urinary 11-deoxy17-hydroxycorticoids

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The present study does not permit any conclusions whether the observed increase in the excretion of 11-deoxy-corticoids represents only a temporary or a more longlasting derangement in the synthesis of adrenocortical hormones. The increase in the excretion o f this steroid fraction persisted in most cases throughout the course of the study. The period of observation was admittedly short, and the depression and anxiety ratings in many cases were still above normal at the time when the steroid excretion pattern was re-examined. Moreover the depression and anxiety scores measure primarily the patient's own evaluation of his emotional state and are not necessarily related to definitive recovery from depression. More prolonged longitudinal studies of the excretion of urinary corticoid fractions during the course of depressive illness would seem to be worthwhile. The l l-oxy-17-hydroxycorticoids which were assayed during the course o f the present investigation represent on the other hand normal 11-oxygenated end products of h o r m o n e synthesis in the adrenal cortex. Although the excretion of this steroid fraction was found to be increased in a few individual depressive patients the average excretion values o f the depressive men or the depressive women as a group did not differ from those observed in the control subjects. This is in accordance with the observed pattern of excretion of urinary total 17-OHCS in depressive patients, which we found to be only slightly more pronounced in the depressive patients than in the control subjects [8]. Although signs of increased adrenocortical function have often been observed during the course of depressive illness, it has recently been pointed out

Excretion of urinary 11-oxy-17-hydroxy-corticosteroidsin depressive patients

371

[7] that depressive patients can be divided into subgroups according to observed behaviour and urinary 17-OHCS levels. One group with high depression ratings during the course of this study showed urinary 17-OHCS levels which were 3-5 times the normal, while other groups with similar depression ratings showed normal or low mean 17-OHCS levels. In addition patients with fluctuating behaviour were found to have fluctuating 17-OHCS levels which showed a high positive correlation with the depression and anxiety ratings observed during the course of hospitalization. It is thus conceivable that depressive patients as a group do not necessarily show signs of an increased cortisol secretion as measured by the urinary exretion of total 17-OHCS or 1 l-oxygenated steroids during a certain point of the course of their illness. Moreover many patients with only mild symptomatology were included in the present study and these individuals probably had no noteworthy derangements of adrenocortical function. The correlation between the excretion of urinary steroids in depressive illness and the changes of depression and anxiety ratings during the course of the illness deserves further comment. In the previous part of the present investigation an attempt was made to correlate the excretion of urinary total 17-OHCS in a group of depressive patients with the depression and anxiety scores obtained in the same individuals on admission to the hospital and following treatment of the depression. The initial excretion of urinary 17-OHCS on admission to the hospital was found to be significantly correlated with the recovery from depressive illness as manifested by the normalization of the elevated depression and anxiety ratings which was observed after one month of treatment. The decrease of the depression and anxiety scores was particularly pronounced in the depressive patients who showed high initial 17-OHCS levels before the initiation of treatment. During the course of the present study a similar comparison was made between the excretion of the 11-oxy- and 11-deoxy-fractions of urinary corticoids which was determined in the same individuals and between the results of the depression and anxiety ratings. A significant positive correlation was also in this case found to exist between the basal excretion of 1 l-oxy-17-hydroxycorticoids before the initiation of treatment and the decrease of both depression and anxiety ratings one month later. It should be noted, however, that although a concomitant decrease of the excretion of the 11-oxygenated corticoids and the anxiety rating could be demonstrated in many cases other patients did not conform to this pattern. This agrees with the observations of Bunney et al. [7] who showed a significant correlation between the excretion of urinary 17-OHCS and anxiety ratings only in the subgroup of depressive patients with fluctuating behaviour. Gibbons and McHugh [3] also noted elevated pretreatment plasma 17-OHCS levels in retarded depressives with high depression ratings who did not show any signs of anxiety. It would thus seem that although an increase of adrenocortical function in terms of elevated plasma cortisol levels or an increased excretion of urinary 17-OHCS is a well-known feature of anxiety [5], other factors must be taken into consideration in explaining the observed variations of adrenocortical function during the course of depressive illness. The response of the adrenal cortex to the blocking effect of methopyrapone, which is an indirect measure of the A C T H secreting capacity of the anterior pituitary, was measured both in terms of the total output of the ll-deoxy-corticoids and as the increment in the excretion of this steroid fraction following the administration of the

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T. JAKOBSON,A. STENB,~CK, L. STRANDSTRt3Mand R. RIM6N

blocking agent. When the response to methopyrapone was measured as an increment of the 11-deoxy-corticoid output, in the depressive males prior to treatment it was found to be significantly less than in the depressive females or in the control subjects. This is apparently a consequence of the increased basal excretion of 11-deoxy-corticoids which was observed in the same group of patients. This finding would seem to be in accordance with a postulated defect of cortisol synthesis in depressive illness in that if the normal synthesis of adrenocortical streoids is primarily altered, the administration of methopyrapone cannot be expected to increase the excretion of 11-deoxygenated steroids beyond a certain point. The increment of the said steroid fraction remains small, despite a total 11-deoxy-corticoid output which can be of a similar magnitude to that observed in normal subjects. Whether the slightly diminished average response to methopyrapone in terms of total excretion of 11-deoxy-corticoids found in depressive males represents a true decrease of the A C T H secretory capacity of these individuals is open to question. In depressive females the methopyrapone response in terms of the total excretion of ll-deoxy-corticoids prior to treatment was slightly more pronounced than in the control subjects. The reasons for this discrepancy are not clear. A hyperactive response to the administration of methopyrapone was seen in a few individual patients prior to the treatment of the depressive illness. This probably reflects an increased A C T H secretion produced in these individuals by the emotional stress of the depressive illness, and would seem to be in accordance with the increase of the basal excretion of urinary 17-OHCS or 11-oxy-17-hydroxycorticoids which was often observed in the same individuals. The hyper-reactive response to the administration of methopyrapone was found to decrease in most cases following treatment, at the same time as the elevated depression and anxiety ratings. It can be concluded that different kinds of alterations of adrenocortical function occur during the course of depressive illness. In our previous investigation [8] different degrees of adrenocortical activity were demonstrated in depressive subjects and two types of patients were found to exist, one with an increased excretion of urinary total 17-hydroxycorticoids, and one with no increase of urinary corticoid excretion. The results of the present study seem to suggest that an increased excretion of derivatives of those adrenocortical hormones which are known to be usually associated with various forms of emotional as well as physical stress [23] and which also often although not invariably are excreted in excessive amounts in depressive patients, does not represent the only derangement of adrenocortical function in depression. In addition an increased excretion of such derivatives of adrenocortical steroids which reflect alterations in the normal synthesis of adrenocortical hormones can be demonstrated in these patients. This suggests a new kind of derangement of adrenocortical function in depression which so far has received little attention. The results of the present investigation would seem to indicate the importance of further observations concerning the qualitative as well as the quantitative aspects of alterations of adrenocortical steroid secretion in affective illness and from these observations further theoretical as well as clinical implications might arise. SUMMARY Fractionation of urinary 17-hydroxycorticoids into 11-oxy-and 11-deoxy-fractions by means of thin layer chromatography was carried out in 16 hospitalized patients

Excretion of urinary 1l-oxy-17-hydroxy-corticosteroids in depressive patients

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suffering f r o m various degrees of depressive illness and in a comparable g r o u p of control subjects. The degree of depression was measured by means o f Beck's Depression Inventory; in addition the Taylor's Manifest Anxiety Scale was determined. Both tests were performed concomitantly with the determination of urinary steroid excretion on admission to the hospital and repeated after one m o n t h of treatment. The average excretion of urinary 11-deoxy-17-hydroxycorticoids in depressive men was f o u n d to be b o t h on admission to the hospital and following treatment significantly higher than in the controls, while a significant increase o f the same steroid fraction was observed in the depressive w o m e n only following treatment o f the depression. The average excretion o f 11-oxy-17-hydroxycorticoids in both sexes was found to be similar as that in the control subjects. W h e n the response to m e t h o p y r a p o n e was determined in depressive patients in terms of the increment of 11-deoxy-17-hydroxycorticoids following the administration o f the blocking agent a low response was observed in the depressive males as a result of the high basal excretion of the 11-deoxy fraction observed in the same patients. The total excretion o f urinary 11-deoxy-17-hydroxycorticoids during the administration of m e t h o p y r a p o n e in the same group of patients was only slightly less than in the control subjects, and in the depressive w o m e n the m e t h o p y r a p o n e response was not found to be significantly different f r o m normal. A significant correlation between the decrease of the depression and anxiety ratings following treatment of the depressive illness and the pre-treatment level of urinary 1 loxygenated corticoids was observed. The l l - d e o x y fraction on the other hand was f o u n d to be correlated only to the decrease o f the anxiety ratings following treatment. The results of the present investigation show that derangements o f the normal synthesis of adrenocortical h o r m o n e s must p r o b a b l y be taken into consideration in depressive illness in addition to the alterations of adrenocortical function which result f r o m an increased production of those steroids which are normally associated with various forms of emotional stress. REFERENCES 1. GIBBONSJ. L., GIBSONJ. G., MAXWELLA. E. and WILLCOXD. R. An endocrine study of depressive illness. J. Psychosom. Res. 5, 32 (1960). 2. BOARDF., WADESONR. and PERSKYH. Depressive affect and endocrine functions. Arch. Neurol. Psyehiat., Chicago 78, 612 (1957). 3. GmaoNs J. L. and McHu6H P. R. Plasma cortisol in depressive illness. J. Psyehiat. Res. 1, 162 (1962). 4. GIBBONSJ. L. Cortisol secretion rate in depressive states. General Psyehiat. 10, 572 (1964). 5. PERSKYH. Adrenocortical function during anxiety, In Physiological Correlates of Psychological Disorders. University of Wisconsin Press, Madison (1962). 6. KURLANDH. D. Steroid excretion in depressive disorders. General Psychiat. 10, 554 (1964). 7. BUNNEYW. E. JR., MASONJ. W. and HAMB~JROD. A. Correlation between behavioral variables and urinary 17-hydroxycorticosteroids in depressed patients. Psychosom. Med. 27, 299 (1965). 8. STENB.~CKA., JAKOBSONT. and RIM6N R. Depression and anxiety ratings in relation to the excretion of urinary total 17-OHCS in depressive subjects. J. Psychosom. Res. 9, 355 (1966). 9. BECKA. T., WARD C. H., MENDELSONM., MOCK J. and ERBAUGHJ. An inventory for measuring depression. Arch. Gen. Psyehiat. 4, 561 (1961). 10. TAYLORJ. A. A personality scale of manifest anxiety. J. Abnorm. (Soc.) Pyschol, 48, 285 (1953). 11. APPLEBYJ. I., GIBSON G., NORYMBERSKYJ. K. and STVBBSR. D. Indirect analysis of corticosteroids. I. The determination of 17-hydroxycortisosteroids. Biochem. J. 60, 453 (1955). 12. HILLE. E. Chromatography of the 17-ketogenic steroids in the diagnosis and control of congenital adrenal hyperplasia. Acta Endocr., Copenhagen 33, 230 (1960).

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13. EDWARDS R. W. H., KELLIE A. E. and WADE A. P. The excretion and oxidation of urinary steroid conjugates. Memoirs of the Society for Endocrinology No. 2. Cambridge University Press, London (1953). 14. EDWARDS R. W. H., MAKIN H. L. J. and BARRATT T. M. The steroid ll-oxygenation index; A rapid method for use in the diagnosis of congenital adrenal hyperplasia. J. Endocrin. 30, 181 (1964). 15. FEW J. D. A method for the analysis of urinary 17-hydroxycorticosteroids. J. Endocrin. 22, 31 (1961). 16. PESONEN S., JAKOBSON T., STRANDSTOM L. and LAMBERG B-A. Unpublished communication (1965). 17. PESONEN S. Estimation of dehydroepiandrosterone and epiandrosterone in clinical hormone analyses. Acta Endocr. Copenhagen 40, 387 (1962). 18. LIDDLE G. W., ESTEP H. L., KENDALL J. W. JR., WILLIAMSW. C. JR. and TOWNES A. W. Clinical application of a new test of pituitary reserve. J. Clin. Endoerin. 19, 875 (1959). 19. FERGUSONH. C., BARTRAMA. C. G., FOWLIE H. C., CATHRO D. M., BIRCHALLK. and MITCHELL F . L . A preliminary investigation of steroid excretion in depressed patients before and after electro-convulsive therapy. Acta Endocr. Copenhagen 47, 58 (1964). 20. BRICAIREU., AUBERT P. and LAUDAT PH. Congenital adrenal hyperplasia due to disturbance in 1 lfl-hydroxylation. Presse M~d. "71, 265 (1963). 21. BROOKS R. V., MATTINGLY U., MILLS I. H. and PRUNXY F. T. G. Postpuberal adrenal virilism with biochemical disturbance of congenital type of adrenal hyperplasia. Brit. Med. J. 1,1294 (1960). 22. GUIGNARD-DEMAYER J. A., CRIGLER J. F. JR. and GOLD N. I. Alterations in cortisol metabolism in patients with Cushing's syndrome and bilateral adrenal hyperplasia. J. Clin. Endocrin. 23, 1271 (1963). 23. HILL S. R. JR., GOETZ F. C., FOX H. M., MURAWSKI B. J., KRAKAUER L. J., REIFENSTEIN R. W., GRAY S. J., REDDY W. J., HEDBERG S. E., ST. MARC J. R. and THORN G . W . Studies on adrenocortical and psychological response to stress in man. Arch. Intern. Meal. 97, 269 (1956).