0021-972X/97/$03.00/0
Journal of Clinical Endocrinology and Metabolism
Copyright © 1997 by The Endocrine Society
Vol. 82, No. 10
Printed in U.S.A.
Prophylactic Adrenalectomy of a Three-Year-Old Girl
with Congenital Adrenal Hyperplasia: Pre- and
Postoperative Studies*
DANIEL F. GUNTHER, TIMOTHY P. BUKOWSKI, E. MARTIN RITZÉN,
ANNA WEDELL, AND JUDSON J. VAN WYK
Division of Pediatric Endocrinology (D.F.G., J.J.V.W.) and the Section of Pediatric Urology (T.P.B.),
University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599; and the
Institutes for Women and Child Health and Molecular Medicine, Karolinska Institute (E.M.R., A.W.),
Stockholm, Sweden
ABSTRACT
Long term follow-up studies of children with congenital adrenal
hyperplasia have documented less than desirable outcomes, including
reduction in final adult height, obesity, virilism, and decreased fertility. We have proposed that children with the most severe forms of
congenital adrenal hyperplasia would be better off if their adrenals
were removed at an early age. We report here on our experience with
prophylactic bilateral adrenalectomy in a 3-yr-old girl with a double
null mutation of the CYP21 gene. The results of sodium balance
studies, performed preoperatively on our patient and her unaffected
fraternal twin sister, and hormonal data are presented as well. In
contrast to her twin, who markedly increased her sodium retention in
response to ACTH, our patient showed increased natriuresis, suggesting a deleterious effect of her adrenals on sodium homeostasis.
Adrenalectomy was carried out at the time of necessary genital repair.
No surgical or postsurgical complications were encountered. (J Clin
Endocrinol Metab 82: 3324 –3327, 1997)
T
concurrently with reconstruction of her genital anomalies.
This marks the beginning of a study to compare the long term
outcome of patients treated with bilateral adrenalectomy to
that of conventionally treated controls. Before surgery, we
compared our patient’s steroid and natriuretic responses to
ACTH stimulation to those of her normal fraternal twin
sister. The normal twin responded to ACTH with marked
sodium retention, whereas our patient responded to ACTH
with increased sodium loss. These findings again demonstrate that adrenals of patients with CAH may actually increase the risk of salt-losing crises in times of stress.
HE MEDICAL treatment of congenital adrenal hyperplasia (CAH) has not been substantially altered since
the introduction of cortisol in the early 1950s despite reports
of less than optimal outcomes. Treatment is complicated by
the difficulty inherent in suppressing adrenal androgens
with dosages of gluco- and mineralocorticoids that are in the
physiological range. Alternating cycles of androgen and glucocorticoid excess often lead to attenuation in growth, obesity, virilization, and precocious or delayed puberty (1–3).
Adult women frequently have menstrual abnormalities, hirsutism, reduced bone mineralization, and decreased fertility
(4, 5). We have proposed that girls with severe forms of CAH
could be more easily managed and would enjoy a better
quality of life if their adrenals were removed at an early age
and they were then managed like other patients with primary
adrenal insufficiency (6). This should permit these children
to attain their full growth potential without the struggle
against obesity and virilization that is inherent in our current
medical approach. The rationale as well as the pros and cons
of such a surgical alternative have recently been debated in
this journal (6).
We report here our experience with the first such prophylactic adrenalectomy in a 3-yr-old girl with a double null
mutation of the 21-hydroxylase gene (CYP21), carried out
Received March 28, 1997. Revision received June 2, 1997. Accepted
June 16, 1997.
Address all correspondence and requests for reprints to: Judson J.
Van Wyk, M.D., Division of Pediatric Endocrinology, CB #7220, 509
Burnett-Womack, University of North Carolina, Chapel Hill, North
Carolina 27599-7220.
* This work was supported in part by a grant (RR-00046) from the
General Clinical Research Centers program of the Division of Research
Resources, NIH.
Case Report
LZ is a 3.1-yr-old white female with 21-hydroxylase deficiency diagnosed prenatally by amniocentesis. Prenatal
evaluation was prompted by the clinical diagnosis of CAH
in an older brother, who had presented at 2 weeks of age with
severe salt-wasting. This first child became ill and died suddenly at 18 months of age. The cause of death was never
determined. In the subsequent clomiphene-induced pregnancy, the mother was found to be carrying twins, and amniocentesis was carried out at 15 weeks gestation under ultrasound guidance. Elevated 17-hydroxyprogesterone (17OHP) and androstenedione levels in LZ’s amniotic fluid
(2245 and 391 ng/dL, respectively) were diagnostic for CAH
(7). Her twin AZ’s levels were not considered diagnostic. In
the hopes of limiting clitoromegaly, treatment of the mother
with dexamethasone (20 mg/kgzday) was initiated during the
17th week of gestation and continued until term.
At birth, LZ was significantly virilized (Prader stage 4).
Her fraternal twin, AZ, was anatomically normal. Using allele-specific PCR (8), it was determined that LZ had inherited
3324
ADRENALECTOMY FOR 21-OH DEFICIENCY
a complete deletion of the CYP21 gene from her father and
an R356W mutation from her mother. This latter point mutation is consistently associated with the most severe, saltwasting form of CAH and has been shown to totally inactivate 21-hydroxylase activity in transfected COS cells (9).
Consequently, LZ is hemizygous double null for CYP21. Her
twin AZ, like their mother, is heterozygous for the R356W
mutation.
The girls were born at 37 weeks gestation. At 3 days of age,
LZ’s 17-OHP level was 19,805 ng/dL. After initial adrenal
suppression, LZ was treated with cortisone acetate by injection ranging in dosages from 16 –22 mg/m2zday. At 14
months of age she was switched to oral hydrocortisone. She
also received fludrocortisone (0.1– 0.15 mg/day). On four
occasions between 7 weeks and 33 months, she required dose
adjustment or short course dexamethasone for incomplete
adrenal suppression, as evidenced by 17-OHP levels ranging
from 1,470 –10,925 ng/dL. Growth and development, however, remained normal. At the time of the study, when LZ
was 3 yr, 1 month, her height was at the 50th percentile,
weight was at the 25th percentile, and her skeletal age was
the same as her chronological age.
Adrenalectomy was performed through bilateral subcostal incisions just before clitoral reduction/recession and exteriorization of the vagina. The two procedures, performed
under a single exposure to general anesthesia, were accomplished without difficulty. No complications were encountered either at the time of surgery or postoperatively, and the
hospital stay (3 days) was not lengthened by the addition of
adrenalectomy. LZ is currently being maintained on 10 mg/
m2zday hydrocortisone and 0.05 mg/day fludrocortisone.
3325
Results
Both girls remained generally well, active, and playful
throughout the study, and there were no substantial fluctuations in their weights or vital signs. There were also no
significant differences between the girls in serum electrolytes
and blood counts; both parameters remained within normal
limits.
Figure 1 shows the 24 h sodium balance during the study.
Both twins maintained similar positive sodium balance on
the 3 control days before ACTH treatment. However, after
ACTH stimulation, AZ’s sodium excretion decreased significantly, increasing her positive balance (135.5 mEq/24 h),
whereas LZ responded with increased sodium diuresis,
resulting in a small negative balance by day 5 (27.1
mEq/24 h).
The differences in plasma levels of cortisol and 17-OHP in
LZ and AZ under basal conditions and at 1 and 6 h after
ACTH are shown in Table 1. Also shown are the results of
a similar test on LZ 5 months after adrenalectomy. Five
months after adrenalectomy, the ACTH level in LZ had risen
significantly (1756 pg/mL), and the 17-OHP level was still
measurable (38 –54 ng/dL), although the 17-OHP level did
not rise in response to exogenous ACTH, and urinary pregnanetriol was unmeasurable in a 24-h urine specimen. Nine
months after surgery, 17-OHP levels had fallen to less than
10 ng/dL, and ACTH had decreased to 186 pg/mL. The only
change in management since her earlier postoperative studies was in dividing her hydrocortisone (10 mg/m2) between
two rather than three doses per day.
Discussion
The most compelling objection to adrenalectomy for CAH
is no longer fear of the surgical procedure itself, but rather
Materials and Methods
In the week before LZ’s adrenalectomy, both girls were admitted to
the University of North Carolina General Clinical Research Center
(GCRC) to compare their steroid and natriuretic responses to ACTH
stimulation. To more nearly approximate physiological replacement, 10
days before admission the dosage of hydrocortisone taken by LZ was
reduced from 15 to 10 mg/m2zday in three divided doses. This, along
with her usual dose of 0.1 mg fludrocortisone each morning, was continued throughout the study.
On admission to the GCRC, the girls were placed on identical diets
that contained 72 mEq/day sodium. After 2 days of adjustment to this
diet, sodium balances, based on dietary intake minus urinary excretion,
were calculated daily for the next 5 days. On the morning of day 4, as
a means of simulating stress, both girls received the ACTH analog
cosyntropin (Cortrosyn, Organon, West Orange, NJ); 0.25 mg, iv, every
6 h for a total of four doses. The first dose was administered after
drawing blood for basal electrolytes, complete blood count, cortisol,
17-OHP, and ACTH. These were repeated at 1 and 6 h. Five months after
adrenalectomy, LZ returned to the GCRC for a repeat of the ACTH
stimulation test. These blood samples were obtained under conditions
of considerable stress due to difficulties in obtaining venous access. Basal
ACTH and 17-OHP levels were also repeated 9 months after surgery.
This sample was obtained while LZ was anesthetized for a urological
procedure.
Approval of all pre- and postoperative studies in the subject and her
normal control as well as adrenalectomy were approved by the committee on the protection of the rights of human subjects at the University
of North Carolina, Chapel Hill. Informed consent was obtained from
both parents.
FIG. 1. Sodium balance over 5 days of study. Sodium intake was
calculated based on the amount of food offered less that returned to
the metabolic kitchen (white bars). Sodium output was measured in
24-h urine samples (amount subtracted from the top of the white
intake bars). The resultant balance is represented by solid bars (LZ)
and cross-hatched (AZ). ACTH caused marked sodium retention in
AZ, increasing positive balance. LZ experienced increased natriuresis, resulting in negative balance after ACTH.
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GUNTHER ET AL.
TABLE 1. Basal and ACTH-stimulated hormone levels before and
5 and 9 months after surgery
LZ received her morning dose of hydrocortisone and fludrocortisone
approximately 1 h before the preadrenalectomy study and 2 h before the
postadrenalectomy study. The 5 month postadrenalectomy sample was
obtained under conditions of considerable stress. The unstimulated 9
month sample was obtained at noon while the patient was asleep.
Preadrenalectomy
Postadrenalectomy
5 months
Basal
1h
6h
Basal
1h
6h
Cortisol (mg/dL)
LZ
8.2
5.1
,1.0
2.3 1.1 ,1.0
AZ
17.7 33.8
5.7
17-OHP (ng/dL)
LZ
713
692
1208
54
38
48
AZ
64
275
61
ACTH (pg/mL)
LZ
145
1756
AZ
36
9
months,
noon
,10
186
the suspicion that adrenalectomy might deprive these patients of some residual adrenal function protecting them in
times of stress. The purpose of this preoperative study was
to determine whether our patient’s impaired adrenals were
capable of affording any protective function under conditions of simulated stress or whether, as previously suggested,
they might actually accentuate adrenal crises by promoting
salt loss. The fact that our patient with CAH had an unaffected fraternal twin sister, afforded a unique opportunity to
directly compare the effects of ACTH stimulation on sodium
balance and steroid secretion under controlled conditions in
these otherwise very similar siblings.
LZ’s increased natriuresis after ACTH treatment, in contrast to the salt retention of her sister, supports the hypothesis
that individuals with complete forms of CAH have a paradoxical salt-losing response to stress. This is in agreement
with previous studies in patients with CAH and in studies
of healthy adults demonstrating salt-wasting after the administration of such adrenal steroids as 17-OHP, 16-hydroxyprogesterone, or progesterone (10). Sodium diuresis is
thought to result when resistance to exogenous gluco- and
mineralocorticoids is caused by competitive inhibition of
steroid receptors from hyperstimulated adrenal steroid intermediates and metabolites. Although LZ’s baseline
17-OHP level indicates less than perfect control at the time
of the study, the levels after ACTH stimulation were well
short of those reported in untreated patients with CAH (11).
Had LZ suffered a crisis during a period of noncompliance
or complete escape from control, it is likely that natriuresis would have been more significant and perhaps
life-threatening.
Five months after adrenalectomy, LZ demonstrated significantly elevated ACTH and measurable 17-OHP levels.
The elevated ACTH level may in part be due to the severe
stress experienced by LZ after several failures to gain iv
access. Four months later, in a sample obtained while LZ was
asleep, 17-OHP was undetectable, and ACTH had fallen to
a more modest level. Nevertheless, these findings reinforce
concerns that activation of abnormal adrenal steroidogenesis
might recur if adrenal rests are present in the ovaries or
elsewhere. Ectopic adrenal tissue has been demonstrated in
testes in adult males with CAH (12) and has been found in
normal children in multiple locations from the diaphragm to
the pelvis (13). It has also been suggested as the cause of
renewed virilization in two girls with CAH who were adrenalectomized in late childhood after failure of medical therapy (14, 15). It is not clear how common and how clinically
significant ectopic adrenal tissue is likely to be in postadrenalectomy patients. We will follow our study subjects with
twice yearly ACTH and 17-OHP measurements and, if elevated, with yearly pelvic ultrasound.
Until we gain further postoperative and long term experience in these patients, especially with regard to morbidity
in times of crises and the frequency and significance of adrenal rests, we believe that adrenalectomy should be offered
as experimental therapy only. As girls generally suffer the
most severe sequelae, and those with double null mutations
of the CYP21 gene particularly so, it is logical that they
should be targeted initially. In addition, girls with severe
biosynthetic defects will be significantly virilized at birth,
presenting an opportunity to perform adrenalectomy at a
young age concurrent with necessary genital surgery, as was
done in this case.
Although other forms of experimental therapy are currently being investigated (16), many benefits of bilateral
adrenalectomy, performed at an early age in patients with
severe 21-hydroxylase deficiency, can be confidently predicted. With an end for the need to suppress adrenal androgens, the common cycle of escape from control, followed by
repeated courses of high dose steroids, should be a thing of
the past. The need for frequent clinic visits and laboratory
evaluation should also be reduced. As long as physiological
replacement of necessary adrenal steroids is maintained, and
as long as significant activation of adrenal rests does not
occur, one would expect normal growth and development in
children and normal ovulation and fertility in women.
Acknowledgments
We thank Don K. Nakayama for his assistance with the surgery, and
Ali S. Calikoglu for help in preparation of the manuscript.
References
1. Pang S, Kenny F, Foley T, Drash A. 1977 Growth and sexual maturation in
treated congenital adrenal hyperplasia. In: Lee P, Plotnick L, Kowarski AA,
Migeon C, eds. Congenital adrenal hyperplasia. Baltimore: University Park
Press; 233–246.
2. Winter J, Couch R. 1985 Modern medical therapy for congenital adrenal
hyperplasia. A decade of experience. Ann NY Acad Sci. 458:165–173.
3. Pescovitz OH, Comite F, Cassorla F, et al. 1984 True precocious puberty
complicating congenital adrenal hyperplasia: treatment with luteinizing hormone-releasing analog. J Clin Endocrinol Metab. 58:857– 861.
4. Helleday J, Siwers B, Ritzèn EM, Carlstrom K. 1993 Subnormal androgen and
elevated progesterone levels in women treated for congenital virilizing 21hydroxylase deficiency. J Clin Endocrinol Metab. 76:933–936.
5. Holmes-Walker DJ, Conway GS, Honour JW, Rumby G, Jacobs HS. 1995
Menstrual disturbances and hypersecretion of progesterone in women with
congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin Endocrinol (Oxf). 43:291–296.
6. Van Wyk JJ, Gunther DF, Ritzèn EM, et al. 1996 The use of adrenalectomy
as treatment for congenital adrenal hyperplasia. J Clin Endocrinol Metab.
81:3180 –3190.
7. Pang S, Levine LS, Cederqvist LL, et al. 1980 Amniotic fluid concentrations
of D5 and D4 steroids in fetuses with congenital adrenal hyperplasia due to
21-hydroxylase deficiency and in anencephalic fetuses. J Clin Endocrinol
Metab. 51:223–229.
8. Wedell A, Luthman H. 1993 Steroid 21-hydroxylase deficiency: two additional
ADRENALECTOMY FOR 21-OH DEFICIENCY
mutations in salt-wasting disease and rapid screening of disease-causing mutations. Hum Mol Genet. 2:499 –504.
9. Higashi Y, Hiromasa T, Tanae A, et al. 1991 Effects of individual mutations
in the P-450(C21) pseudogene on the P-450 activity and their distribution in the
patient genomes of congenital steroid 21-hydroxylase deficiency. J Biochem
(Tokyo). 109:638 – 644.
10. Janowski A. 1977 Naturally occurring adrenal steroids with salt losing properties: relationship to congenital adrenal hyperplasia. In: Lee P, Plotnick L,
Kowarski AA, Migeon C, eds. Congenital adrenal hyperplasia. Baltimore:
University Press; 99 –112.
11. New MI, Lorenzen F, Lerner AJ, et al. 1983 Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab.
57:320 –326.
3327
12. Kirkland RT, Kirkland JL, Keenan BS, Bongiovanni AM, Rosenberg HS,
Clayton GW. 1977 Bilateral testicular tumors in congenital adrenal hyperplasia. J Clin Endocrinol Metab. 44:369 –378.
13. Okur H, Kucukaydin M, Kazez A. 1995 Ectopic adrenal tissue in the inguinal
region of children. Pediatr Pathol Lab Med. 15:763–767.
14. Zachman M, Manella B, Kempken B, Knorr-Muerset G, Atares M, Prader A.
1984 Ovarian steroidogenesis in an adrenalectomized girl with 21-hydroxylase
deficiency. Clin Endocrinol (Oxf). 21:575–582.
15. von Mühlendahl K, Sippell W. 1989 Adrenalektomie als therapie bei schwer
einstellbarem adrenogenitalen syndrom. Monatsschr Kinderheilkd.
137:341–344.
16. Merke DP, Cutler GB. 1997 New approaches to the treatment of congenital
adrenal hyperplasia. JAMA. 277:1073–1076.