The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 2 482-484
Copyright © 2001 by The Endocrine Society
Fertility and Body Composition after Laparoscopic Bilateral Adrenalectomy in a 30-Year-Old Female with Congenital Adrenal Hyperplasia
Hilgo Bruining,
Atte H. Bootsma,
Jan W. Koper,
Jaap Bonjer,
Frank H. de Jong and
Steven W. J. Lamberts
Departments of Medicine (H.B., A.H.B., J.W.K.) and Surgery (J.B.),
University Hospital Rotterdam, 3000 CA Rotterdam; and Department of
Medicine (F.H.d.J., S.W.J.L.), Erasmus University Rotterdam, 3000 DR
Rotterdam, The Netherlands
Address correspondence and requests for reprints to: Dr. Atte H. Bootsma, Department of Medicine, Room D430, University Hospital Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail:
bootsma{at}inw3.azr.nl
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Abstract
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Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is
caused by an inborn defect in the 21-hydroxylase gene
(CYP21), leading to virilization of female patients and
causing ambiguous genitals in the majority of female infants. Adult
women may suffer from loss of libido, irregular or absent cycles, and
reduced fertility, despite intensive medical treatment. These problems
have stimulated the search for alternative treatment modalities. We
present an adult female patient, who was difficult to treat medically
and whose clinical situation markedly improved after laparoscopic
bilateral adrenalectomy. The procedure was well tolerated and without
side effects. Postoperatively the elevated serum progesterone and
17-hydroxyprogesterone levels, as well as the undetectable LH levels,
normalized. The procedure resulted in marked clinical improvement.
Within 12 months after surgery she lost 11 kg in weight. This weight
loss consisted mainly of adipose tissue. Acne disappeared, and she had
a regular 4-week menstrual cycle, with progesterone levels that are
compatible with a luteal phase. The introduction of laparoscopic
techniques may give an impulse to the application of surgical therapy
at a larger scale in patients with 21-hydroxylase deficiency who are
difficult to treat with adrenal suppression therapy.
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Introduction
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CONGENITAL ADRENAL hyperplasia (CAH) due to
21-hydroxylase deficiency is caused by an inborn defect in the
21-hydroxylase gene (CYP21; Refs. 1, 2, 3). This
gene is normally expressed in the adrenal glands. The genetic defect
causes a deficit in functionally active enzyme, leading to the
inability to synthesize mineralo- and glucocorticosteroids. Depending
on the type of defect, the level of residual enzyme can range from a
subtle reduction to complete absence. The decreased synthesis of
cortisol results in increased secretion of ACTH from the pituitary,
with subsequent adrenal hyperplasia and overproduction of
21-hydroxylase substrates, which can be further metabolized to
androgenic steroids, leading to virilization of female patients and
causing ambiguous genitals in the majority of female infants. Growth is
initially accelerated, followed by early epiphysial closure and short
stature in both sexes (4, 5, 6). Hyperandrogenism of adrenal
origin can induce precocious puberty in boys. The medical treatment of
21-hydroxylase deficiency has not been substantially altered since 1950
(7).
Glucocorticoid replacement aims to reduce virilization by
suppression of ACTH stimulation. The reported prescribed dosages
frequently exceed 15 mg cortisol/m2/day, whereas
the normal daily secretion rate is about 7–8
mg/m2 (8, 9). Despite frequent
monitoring and dose adjustments these supraphysiological dosages have
been shown to lead to adverse effects like attenuation of growth,
obesity, and decreased bone mineral density (10, 11, 12, 13). In
adult life sexual functioning is often impaired, both biologically and
psychologically (14). Women still suffer from loss of
libido, irregular or absent cycles, and reduced fertility (6, 15, 16, 17). In males suppression of gonadotrophic hormones may
induce poor spermatogenesis (4).
These problems have stimulated the search for alternative
treatment modalities (9, 18). It is now possible to carry
out prenatal fetal genotyping in women known to be at risk of having
offspring with 21-hydroxylase deficiency, and affected female fetuses
can be treated in utero to prevent virilization. Also,
bilateral adrenalectomy has been used in patients where medical
suppression of adrenal precursors was difficult to achieve or was
accompanied by serious side effects (19, 20, 21, 22). Patients
without any remaining enzyme activity, the so-called double null
mutation carriers, are supposed to be the most eligible candidates for
this approach (9). This invasive treatment has become more
accessible because the patients can be identified easily by genotyping
of the CYP21 gene, and also by the introduction of
laparoscopic adrenalectomy. This procedure is safe, less mutilating,
and well tolerated (23, 24, 25). We present a typical adult
female patient with CAH as a result of complete loss of 21-hydroxylase
activity, who was difficult to treat medically and whose clinical
situation was markedly improved by laparoscopic bilateral
adrenalectomy.
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The patient
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The patient, now a 31-yr-old female, from nonconsanguineous
parents, was born with ambiguous genitalia. She went through a
salt-losing crisis shortly after birth and was diagnosed as
having classical CAH on clinical grounds. At 2 yr of age a
nephropyelotomy and a meatotomy of the urethra were performed to
relieve her from recurrent urinary tract problems. When she was 4 yr
old a clitoral reduction and correction of the labia were performed,
followed by an introitusplasty and vaginoplasty at age 13 and 16,
respectively. She visited the hospital three to four times each year,
and on these occasions circulating hormone levels were checked. The
results were used to adjust the glucocorticoid dose to keep
androstenedione and 17-hydroxyprogesterone levels within in the normal
range using as little medication as possible. Despite this frequent
monitoring and frequent dose adjustments, she experienced many problems
that can accompany the treatment of these patients: she did not feel
feminine, had a masculine build, was obese, had irregular menses with
long amenorrhoic periods, and a seborrhoic skin with acne. Her weight
was 79 kg, and her height was 168 cm, whereas her mother and father
measured 174 and 180 cm, respectively. She was normotensive (110/70 mm
Hg).
Using allele-specific PCR (26) it was determined that the
patient was homozygous for a splice-site mutation in intron 2, which by
itself would have resulted in a very low residual activity of
21-hydroxylase activity (27). In addition, however, the
patient was heterozygous for the five most C-terminal mutations in the
protein: V281 L, Ins T, Q318 ter, R356 W, and P453 S. At the age of 29
she used dexamethasone at a dose varying between 0.5 and 1 mg per day
in two divided doses taken at 0900 and 2100 h and 0.0625 mg/day
fludrocortisone. With those treatment regimens serum progesterone and
17-hydroxyprogesterone concentrations remained well above the reference
levels in our laboratory, whereas serum ACTH levels were normal. A
representative hormonal profile is shown in Table 1
. Furthermore, the LH was suppressed,
which might contribute to the disturbance of her menstrual cycle (Table 1). A computed tomography scan showed bilateral hyperplasia of both the
adrenals.
Laparoscopic biadrenalectomy was offered as alternative treatment, with
the objective to restore the menstrual cycle, reduce masculinization,
and make medical (supplementation) therapy easier and less
intensive.
Adrenalectomy was performed using a standard laparoscopic procedure
(22, 23, 24). The operation and postoperative recovery were
uncomplicated, and discharge from hospital followed after 3 days.
Replacement therapy was started with 10 mg hydrocortisone three times
daily and 0.0625 mg fludrocortisone once daily. Hydrocortisone
replacement was later tapered to 20 mg daily without adverse effects.
However, early morning serum ACTH levels turned out to be increased.
Therefore, hydrocortisone replacement therapy was increased to 25
mg/day, after which ACTH levels normalized (data not shown).
Postoperative laboratory data (Table 1
) revealed that the serum
progesterone and 17-hydroxyprogesterone levels had normalized and
that LH levels became measurable again. The procedure resulted in
marked clinical improvement. Within 12 months after surgery she had
lost 11 kg in weight, her acne had disappeared, and she had a regular
4-week menstrual cycle, with progesterone levels that are compatible
with a luteal phase. This strongly suggests that she ovulated during
her menstrual cycles. Subjective improvement was reported in terms of
increased feeling of well being and femininity. Her physical activity
and capacity were unaltered, subjectively. Body composition and bone
mineral density were assessed by dual-energy x-ray absorptiometry using
a Lunar DPX-L densitometer (Lunar Corp., Madison, WI)
before and after surgery (Table 2). The
results show that loss of fat completely accounted for her weight loss.
Lean body mass and bone mineral density did not change.
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Discussion
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Here, we report the excellent clinical effect of bilateral
laparoscopic adrenalectomy in an adult female with classical CAH. The
patient, like many of her fellow patients, had experienced virilizing
and masculinizing effects from birth to adulthood, despite intensive
follow-up and variable doses of medical treatment. Recently,
laparoscopic adrenalectomy was introduced as a new modality for
surgical treatment. The availability of ample local expertise with this
procedure for different indications (24) helped us with
the decision to offer our patient bilateral adrenalectomy as the
alternative for the medical treatment of the sequelae of her CAH. This
procedure would completely deprive her of all adrenal steroid hormone
precursors and their (masculinizing) effects. Earlier studies have
shown that the hyperplastic adrenal is not helpful in times of stress.
It has been demonstrated that adrenal steroid precursors promote salt
wasting under stress conditions in both patients and healthy volunteers
(28). On the other hand, clinically beneficial effects of
steroid precursors have recently been reported for
dehydroepiandrosterone (DHEA): suppletion of
DHEA restored libido in DHEA-deficient
women (29, 30). These findings necessitate careful
follow-up of adrenalectomized women to determine whether
suppletion to physiological dosages of steroid precursors is indicated
to further improve their quality of life. Follow-up is also required
because failure of surgical therapy with recurrence of virilization
several years later has been reported (20). Virilization
in those patients was driven by either ovarian steroidogenesis or
hormone production in ectopic adrenal tissue (20, 21). To
date, the frequency and clinical importance of these failures in
adrenalectomized patients have not been determined. Procedure-related
complications are impressively low in experienced hands (23, 24).
In our patient, a good short-term result was obtained. All preoperative
goals were met, without any complications either related to the
procedure or to the hormonal replacement therapy afterward. This is in
line with the data reported on patients with classic adrenal
hyperplasia who were treated by biadrenalectomy by different techniques
or earlier in their lives (9, 18, 19, 20, 21). The introduction of
laparoscopic techniques may give an impulse to the application of
surgical therapy at a larger scale in cases that are difficult to treat
with adrenal suppression therapy.
Received April 4, 2000.
Revised October 4, 2000.
Accepted October 26, 2000.
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Abstract
Introduction
