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Variable Efficacy of Glucocorticoids in Congenital Adrenal Hyperplasia

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Variable

Efficacy

of Glucocorticoids

in Congenital

Adrenal

Hyperplasia

James W. Hansen, M.D., Ph.D., and D. Lynn Loriaux, M.D., Ph.D.

Franz tile National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

ABSTRACT. We have examined the suppression of urinary

pregnanetriol and 17-ketosteroids during treatment with

cortisol, cortisone, prednisone, and dexamethasone in eight

patients with congenital adrenal hyperplasia. A large

mdi-vidual variation in response to each agent was observed. In

some individuals, cortisone is less effective than its generally

accepted potency would indicate. At equivalent glucocorti-coid dosage, dexamethasone was twice as effective as the

other steroids in suppressing urinary 17-ketosteroids and

pregnanetriol. The potency of dexamethasone in suppressing

adrenal function was 80 times that of cortisol, about twice its generally accepted potency as a glucocorticoid or anti-inflammatory agent. Pediatrics, 57:942-947, 1976, ADRENAL

HYPERPLASIA, CONGENITAL DEFECTS, GLUCOCORTICOIDS,

DEX-AMETHASONE, CORTISONE, PREGNANETRIOL.

Congenital adrenal hyperplasia (CAH) results

from an enzymatic defect in cortisol synthesis.

The impaired ability of the adrenal gland to

produce cortisol enhances adrenocorticotropic hormone (ACTH) release from the pituitary gland and consequent hyperstimulation of intact adre-nal pathways. The resulting hypersecretion of

adrenal steroids other than cortisol may result in

clinical manifestations such as hypertension and/ or virilization and premature closure of the epiphyses.

The logical treatment of this disorder is gluco-corticoid replacement, either with cortisol or an

appropriate analog. Cortisone was one of the

earliest agents used in CAH.’ Although it is rapidly converted to cortisol, we have found that, in some cases, even supraphysiologic doses of cortisone may not adequately suppress urinary

pregnanetriol and 17-ketosteroids. Others have also noted this phenomenon,’’

m

spite of which

we have seen several patients who were being treated unsuccessfully with very high doses of cortisone.

The apparent discrepancy between glucocorti-coids given in purportedly equipotent doses and the variable response in adrenal suppression led

us to investigate the relative adrenal suppressive

activity of four commonly used glucocorticoids in

patients with the 21-hydroxylase variety of

con-genital adrenal hyperplasia. Equivalencies of

cortisol, cortisone, prednisone, and

dexametha-sone are generally accepted as 40, 50, 10, and 1,

corresponding to potency ratios of 1, 0.8, 4, and 40 when compared to cortiso1. These

equivalen-cies were used throughout the following studies.

PATIENTS AND METHODS

Four male and four female patients with 21-hydroxylase deficiency were studied. Two of

these patients had the salt-losing variety of the

disorder. The patients ranged in age from 7#{189}to

23 years, and all stages of puberty were repre-sented. Each patient underwent a six-week study. During the first and last weeks of the study, the patient took his usual medication on his usual

(Received April 29; revision accepted for publication October 9, 1975.)

(2)

TABLE I

CLINICAL DATA ON PATIENT PoPutTIoN#{176}

Sex

Deficiency Diagnosis

Chronological

yr ma

Age

Bone

yr mo

Height

yr mo

Tann

Pubic Hair

er Stage

Gonadal/ Breast

Initial Therapy (mg/day)

Urinary Pregnanetriolt

(mg/gm of creatinine)

F SL-21 7 6 10 0 8 2 I I F 15 8.1

M SL-21 10 0 13 6 11 2 IV II E 50 14.6

M NSL-21 11 0 13 6 13 6 III III E 62.5 2.8

M NSL-21 11 2 16 0 14 0 IV II F 20 28.0

M NSL-21 13 1 15 6 12 6 IV III F 20 23.4

F NSL-21 15 0 16 0 11 6 IV IV F 15 10.8

F NSL-21 20 3 Mature 12 6 IV V L\-1-E 5 6.3

F NSL-21 23 0 Mature 13 0 V V -1-E 5 3.0

0 Abbreviations: SL-21 = salt-losing 21-hydroxylase deficiency; NSL-21 = non-salt-losing 21-hydroxylase deficiency; F =

cor-tisol; E = cortisone; -1-E = prednisone.

t While taking equivalent dosage of cortisol; may be keyed to initial values in Figure 1.

schedule (Table I). During each of the four intervening weeks he took an equivalent dose of a different glucocorticoid, portioned to correspond to his usual times of administration. The different glucocorticoids employed were cortisol, corti-sone, prednisone, dexamethasone, or one half the equivalent dose of dexamethasone. During the last two days of each week, two 24-hour urine specimens were collected and analyzed for crea-tinine,5 17-ketosteroids,6 and pregnanetriol.T The data are expressed as milligrams of steroid per

gram of creatinine to minimize collection errors

and to normalize the data with respect to body size. The results of the two urine specimens collected at the end of each weekly treatment period were averaged for each patient and plotted to show individual steroid excretion

responses to treatment changes. The mean and

standard errors of the group response to each

agent were also calculated.

RESULTS

The steroid determinations made on the two urine specimens from the end of each treatment period were in good agreement. The mean for the

differences derived from each pair of

determina-tions was 2.9 mg/gm of creatinine for both the

17-ketosteroids and pregnanetriol. Similarly, the

urine steroid levels were in good agreement

between the first and last weeks of the study

(

mean difference of 5 mg/gm of creatinine) when the patients were taking their usual medication. Thus, there was nothing to suggest a cumulative effect of the different glucocorticoids given during the intervening weeks.

The mean responses of urinary 17-ketosteroids and pregnanetriol to the equivalent dose of each agent are shown in Figure 1 using data from all

subjects. Dexamethasone was most effective

(

P < .05) and cortisone was least effective in

suppressing adrenal activity when used in gluco-corticoid equivalent doses. Cortisol, prednisone, and dexamethasone at one half the “equivalent dose” were about equally effective.

The average pregnanetriol values are shown for

each patient and agent in Figures 2 and 3. Dexamethasone at “equivalent” glucocorticoid doses most effectively suppressed urinary pregna-netriol in each patient. Two patients were very

refractory to cortisone but responded quite well

to cortisol. Two patients had an equal response to cortisol and cortisone but an increased respon-siveness to prednisone and dexamethasone. Three patients were quite responsive to both cortisol

and cortisone and less responsive to prednisone.

One patient had a maximal response to all of the

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30

17 Ketosteroids

Pregnanetriol

I0

a’

E

FIG. 1. Average urinary steroid levels in eight CAH patients taking “equivalent” glucocorticoid doses of each of the agents indicated on the abscissa. Error bars represent ± 1 SEM.

F = cortisol; E = cortisone; -1-E = prednisone; DEX dexamethasone; DEX/2 = one half dose dexamethasone.

F E -I--E DEX DEX/2

I I I I

1 I

I

F

E

-IE

DEX

DEX/2

FIG. 2. Urinary pregnanetriol response patterns to various glucocorticoids in eight individual CAH patients. Each point represents the average of the pregnanetriol levels in two 24-hour urine specimens collected while the patient was taking the glucocorticoid indicated on the

abscissa.

w

z

z

LU

a:

0

a’

30

20

10

(4)

50

40

30

20

,

% S#{149}

10

F

E

t-’I-E

DEX

DEX/2

PREGNANETRIOL

PER

GRAM

C REATI

NINE

FIG. 3. Urinary 17-ketosteroid response patterns to various glucocorticoids in eight individual CAH patients. Each point represents the average of the 17-ketosteroid levels in two 24-hour urine specimens collected while the patient was taking the glucocorticoid indicated on the

abscissa.

Patterns of 17-ketosteroid excretion were similar

to those seen in pregnantriol, but with less pronounced changes (Fig. 3). These observations are the same whether expressed as milligrams per gram of creatinine or milligrams per 24 hours.

In one patient refractory to cortisone and

moderately responsive to cortisol, the responses to prednisone and prednisolone were evaluated.

Urinary 17-ketosteroid levels were 17 and 21

mg/gm of creatinine when taking prednisone

and prednisolone, respectively, while the pregna-netriol values were 20 and 24 mg/gm of creatin-me; thus, both agents gave very similar degrees of suppression. The response to cortisol, by compar-ison, resulted in ketosteroids of 10 mg and

preg-nanetriol levels of 15 mg/gm of creatinine.

DISCUSSION

A principal objective in the treatment of CAH

is the suppression of inappropriate virilization

and the associated premature closure of epiphyses

with resultant short stature. Monitoring bone age

during therapy provides a useful index of the adequacy of treatment for this purpose. Because

of the inherent difficulties in estimating bone age

and the time required to observe significant

changes, a more sensitive, albeit less direct,

measurement of the efficacy of therapy is adrenal

activity. Urinary 17-ketosteroids have commonly been used to assess adrenal androgen production. The data in Figure 1 suggest that pregnanetriol may be a somewhat more sensitive index of

response to therapy since changes in

pregnane-triol excretion are more marked than the changes in 17-ketosteroid excretion. In this regard, Brook

et at. have shown that relative ability of cortisone

and prednisone to suppress urinary pregnanetriol

correlated well with the relative ability of these

two agents to control growth velocity.”

The refractoriness of two of our patients to

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TABLE II Dnuc COMPARISON Adrenal Suppressive Potency Agent lIa!f-lifc (mimi) Accepted Potency’ , Average Range

(A)rtisol 80 to 100 1 1

-Cortisone 30 0.8 0.4 0.2 to 0.8

Prednisoie 60 4 3 1 to 6

Dexamneth- 200 40 80 30 to 200 asone

Prednisolone 200 5 -

-failure to take the medication, abnormal absorp-tion, or inability to reduce the 1 1-keto moiety. The first two possibilities are ruled out by

observ-ation that 17-hydroxycorticosteriod excretion in

these patients while taking cortisone equalled or

slightly exceeded that when taking cortisol. In

one of these patients, prednisone and predniso-lone were shown to be equally effective,

sug-gesting that reduction of the il-keto moiety

proceeded normally. Thus, the reasons for the failure of cortisone to effectively suppress adrenal

function in some patients with CAH remain

unknown.

The variable adrenal-suppressive response to

different glucocorticoids might be explained by

variation in biological half-life’ (Table II), since

the response might logically be a function of the

hormone level integrated over time. Although the

plasma half-life of cortisone is 30 minutes

compared to 80 to 100 minutes for cortisol, the

biologically effective half-life of the two agents

should be the same since cortisone becomes

biologically active in man through a reduction of

the 1 1-keto group, converting it to cortisol.

Pred-nisone (60-minute plasma half-life) is similarly

converted to the active form, prednisolone

(200-minute plasma half-life). In one patient refractory

to cortisone, it was observed that prednisolone

and prednisone suppressed adrenal activity

equally well but less effectively than cortisol in

equipotent dosages. This is the converse of what

might be expected from their half-lives.

Further-more, the fact that prednisone was more effective

than cortisol or cortisone in two patients and less effective in two others is not consistent with the variability of the effect being due entirely to differences in glucocorticoid half-life.

A difference between adrenal suppressive

activity and peripheral or tissue effects (glycogen deposition, anti-inflammatory activity, nitrogen wasting, and other indicators generally used to establish potency) may be a factor in the variable responses seen in our patients. Using urinary pregnanetriol normalized by urinary creatinine excretion as an indirect measurement of ACTH production, we have estimated the ACTH-sup-pressing potencies of the several preparations used when given in equipotent doses based on “glucocorticoid” activity, as shown in Table II.

The potency ranges emphasize the great degree

of variability among patients. Cortisone, when

given in a dose having a glucocorticoid potency equivalent to cortisol, appears to have about one half the ACTH-suppressing activity of cortisol. On the other hand, this study suggests that when dexamethasone is given in doses of equivalent glucocorticoid potency, the ACTH-suppressing potency is about twice that of cortisol. Other investigators have also shown this enhanced

differentia adrenal suppressive potency of

dexa-methasone with values ranging from 50 to 100’#{176}” while hyperglycemic and anti-inflammatory po-tencies are reported to range from 12 to 3#{216}#{149}IO.1214

The implications of this finding for the treatment

rationale of congenital adrenal hyperplasia have not, to our knowledge, been previously explored. It is possible that adequate adrenal suppression

may be obtained with sufficiently low doses of

dexamethasone to minimize untoward peripheral

effects in CAH patients relatively unresponsive to other glucocorticoids.

RELEVANCE

It would appear that when a patient is refrac-tory to one glucocorticoid (especially cortisone)

another should be considered. Cortisol, being the

physiologic hormone active in man, is a logical choice, but must be given frequently because of its short half-life. This study suggests that dexa-methasone might also be a reasonable choice because such low doses effectively suppress

adrenal steroidogenesis that untoward effects may

be minimized. It should be noted, however, that

the long-term effects of halogenated steroid

administration are unknown, and that many of

the longer acting glucocorticoids have been

directly associated with inhibition of growth.’3”

Halogenated glucocorticoids in dosages necessary

to achieve therapeutic control of allergic

symp-toms resulted in significant growth retardation,

although the dosages used were generally higher on a per kilogram basis.’5 The more potent nonhalogenated steroids have likewise been

asso-ciated with problems of growth and development.

(6)

response to insulin-induced hypoglycemia was

depressed by 6-a-methylprednisolone but

re-turned to normal when treatment was changed to cortisol. In contrast, Sturge et a!. “' did not find

any suppression of growth hormone in children

treated with prednisolone. Similarly, Sperling et 1 and Vasquez et a!. found no significant

effect of cortisone acetate on growth hormone release, although abnormally low growth rates were observed in most of their patients. These

observations suggest that glucocorticoid-induced

growth inhibition may be in part due to a peripheral effect.

SUMMARY

We have concluded that there is large mdi-vidual variation in the ability of the pituitary-adrenal axis to respond to various glucocorticoids in CAH. The commonly used agent, cortisone acetate, may be particularly ineffective in some patients and others have reported difficulty in

achieving adequate control.’ ‘ Cortisol, as the

physiologic hormone, is probably the

drug

of

choice during the growing years since Raiti and

Newns2’ have shown normal growth rates in CAH

when it is used. Cortisol, however, must be given frequently (usually three times each day) and may be replaced by longer acting agents given once or twice per day upon reaching adulthood. When a patient is found to be refractory to physiologic

doses of any given glucocorticoid, or when

management problems arise from frequent

administration of the shorter-acting agents,

dexa-methasone might be considered in view of its

enhanced potency for adrenal suppression. In

such cases, the dose of dexamethasone must be

adjusted to the minimum required for adrenal

suppression, the growth rate must be monitored

scrupulously, and, when salt loss is a feature,

mineralocorticoid replacement may also be

necessary.

REFERENCES

1. Wilkins L, Lewis BA, Klein R, Rosemberg E: Suppres-sion of androgen secretion by cortisone in a case of congenital adrenal hyperplasia: Preliminary report. Bull Johns Hopkins Hosp 86:249, 1950.

2. Bartter FC, Albright F, Farber AP, et a!: The effects of adrenocorticotropic hormone and cortisone in the adrenogenital syndrome associated with congenital adrenal hyperplasia: An attempt to explain and correct its disordered hormonal pattern. J Clin

Invest 30:237, 1951.

3. Wilkins L, Lewis HA, Klein H, et a!: Treatment of

congenital adrenal hyperplasia with cortisone.

J

Clin Endocrinol Metab 1 1: 1, 1951.

4. Lawler DP, Thorn GW: Diseases of the adrenal cortex.

In, Harrison TR, Adams RD, Bennett JO, et a! (eds):

Principles of Internal Medicine, New York,

McGraw Hill Book Co. 1966, p 479.

5. Chasson AL, Grady HJ, Stanley MA: Determination of creatinine by means of automatic chemical analysis. Am J Clin Pathol 35:86, 1961.

6. Sobel E, Golub OJ, Henry RJ, et a!: Study of the Norymberski methods for determination of

17-keto-genie steroids in urine. J Clin Endocrinol Metab

18:208, 1958.

7. Cox RI: A method for the quantitative determination in

urinary extracts of C, 17:20-dihydroxy-20-methyl steroids. Biochem

J

52:339, 1952.

8. Brook CGD, Zachmann M, Prader A, Murset G: Expe-rience with long term therapy in congenital adrenal hyperplasia. J Pediatr 85: 12, 1974.

9. Peterson RE: The miscible pool and turnover rate of adrenocortical steroids in man. Recent Prog Horm Res 15:231, 1959.

10. Burrim

JJ,

Black RL, Lutwak L, et a!: Studies on

dexamethasone, a new synthetic steroid in

rheuma-toid arthritis: A preliminary report-adrenal

corti-cal, metabolic and early effects. Arthritis Rheum

1:313, 1958.

11. Wilkins L: Diagnosis and treatment of congenital virili-zing adrenal hyperplasia. Postgrad Med 29:31, 1961.

12. Boland EW: Antirheumatic potency of chemically modified adrenocortical steroids. Am J Med 31:581, 1961.

13. Lichtwitz A, Hisco D, Gresle C: Malades traites parla dexamethasone comparison avec Ia prednisone et la 6-methyl-prednisolaux. Semin Hop Paris 35:1570, 19J.

14. Ringler I, West K, Dulin W, Boland EW: Biological potencies of chemically modified adrenocorticoste-roids in rat and man. Metabolism 13:37, 1964. 15. Van Metre TE, Niermann WA, Rosen U: A comparison

of the growth suppressive effect of cortisone,

pred-nisone and other adrenal cortical hormones.

J

Allergy 31:531, 1960.

16. Laron Z, Pertzelan A: The comparative effect of 6a fluoroprednisolone, 6a methylprednisolone, and hydrocortisone on linear growth of children with congenital virilism and Addison’s disease. J Pediatr

73:774, 1968.

17. Stempfel RS, Sheikholislarn BM, Lebovitz HE, et a!:

Pituitary growth hormone suppression with low

dosage, long acting corticoid administration. J

Pediatr 73:767, 1968.

18. Sturge HA, Beardwell 0, Hartog M, et a!: Cortisol and growth hormone secretion in relation to linear growth: Patient’s with Still’s disease on different therapeutic regimens. Br Med J 3:547, 1970. 19. Sperling MA, Kenny FM, Schutt-Aine JC, Drash AL:

Linear growth and growth hormonal responsiveness in treated congenital adrenal hyperplasia. Am J Dis

Child 122:408, 1971.

20. Vasquez AM, Schutt-Aine JC, Kenny FM: Effect of cortisone therapy on the diurnal pattern of growth

hormone secretion in congenital adrenal

hyperpla-sia. J Pediatr 80:433, 1972.

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1976;57;942

Pediatrics

James W. Hansen and D. Lynn Loriaux

Variable Efficacy of Glucocorticoids in Congenital Adrenal Hyperplasia

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1976;57;942

Pediatrics

James W. Hansen and D. Lynn Loriaux

Variable Efficacy of Glucocorticoids in Congenital Adrenal Hyperplasia

http://pediatrics.aappublications.org/content/57/6/942

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