| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
EXTENSIVE PERSONAL EXPERIENCE |
Division of Pediatric Endocrinology (J.J.V.W.), The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; and the Division of Pediatric Endocrinology (E.M.R.), Department of Woman and Child Health, Karolinska Institute, S171-76 Stockholm, Sweden
Address all correspondence and requests for reprints to: Judson J. Van Wyk, M.D., Division of Pediatric Endocrinology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. E-mail: judvw{at}med.unc.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The adrenals were removed laparoscopically in 13 patients and by open flank incisions in five. Adrenal crises associated with severe illnesses occurred in five patients at times when their glucocorticoid substitution was suboptimal. All were responsive to appropriate therapy. Two of these patients were young children who had hypoglycemia during gastroenteritis or febrile illness associated with poor food intake or vomiting. Significant elevations of adrenal steroid precursors, presumably from ectopic adrenal rests, were observed postoperatively in eight of the patients.
Patients and parents were nearly unanimous in their enthusiasm for adrenalectomy. In most, signs of androgen excess have decreased, and obesity has become less of a problem with lowering the dose of glucocorticoid. We conclude that adrenalectomy is a safe and efficacious method of managing congenital adrenal hyperplasia in selected patients. Prophylactic adrenalectomy in young children with double null mutations remains experimental.
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
If adrenal androgens are not suppressed, these patients suffer from acne, hirsutism, and in childhood, rapid growth and disproportionate advancement of their bone age. Then, if they are later brought under control, they often undergo true sexual precocity (2). When they are given higher dosages to halt their progressive virilization, they may become progressively obese and develop severe psychosocial problems resulting from their poor self-image. Affected females have pregnancy rates that are far below normal, partly because of the psychological and anatomical problems that make heterosexual attachments difficult, and partly because their elevated progesterone levels act as contraceptives (3). Women with CAH are also more prone to polycystic ovary syndrome (4). It is often not clear how many of these problems are due to noncompliance and how many are due to our limited ability to control ACTH secretion through the feedback mechanism.
Several years ago we suggested that certain patients with CAH would profit from bilateral adrenalectomy, because children with Addison’s disease or adrenal hypoplasia present many fewer problems in management (5). Since then, we have carried out adrenalectomy in three young children with double null mutations of their CYP-21 gene. These were part of a prospective study to compare prophylactic adrenalectomy in the most severely affected children with conventional treatment. Informed consent was obtained in all cases. In addition, we have identified 15 other patients with CAH who, during the past 6 yr, were subjected to bilateral adrenalectomy because of difficulties in management. Thirteen of these patients have been reported in the literature (6, 7, 8, 9, 10, 11, 12, 13, 14). The average duration of follow-up of these 18 patients was 59 months, representing an aggregate of 90 postoperative years. This, therefore, is the first long-term follow-up of patients with CAH treated by bilateral adrenalectomy.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
summarizes preoperative data for each patient, the course before surgery, and the indications for surgery. Table 2 summarizes the overall result of surgery and the evaluations of the procedure by patients and their families. Our greatest emphasis was on documenting any adrenal crises or other severe illness that had occurred after adrenalectomy. Preoperative and postoperative laboratory data were available on most patients but were not systematically analyzed due to the lack of uniformity in the testing methods. Our own three patients are described in more detail.
|
|
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Nine of the 18 patients were 8 yr of age or younger at the time of surgery, and the others ranged in age from 14–44 yr. Sixteen had 21-hydroxylase deficiency (one of whom was late onset), and the other two had 11ß-hydroxylase deficiency. Three of the younger patients had double null mutations of CYP21 and were adrenalectomized prophylactically as part of an approved research protocol. The others were adrenalectomized because attempts to keep their adrenals suppressed had proven ineffective, and they now were showing signs of androgen excess as well as obesity and other signs of hypercortisolism.
The patient with late onset CAH (SD) was born with a meningomyelocele leading to neurogenic bladder and recurrent pyelonephritis. She underwent pubarche at age 5 yr, thelarche at age 7 yr, and menarche at age 14 yr. Late-onset CAH was diagnosed at age 16 yr on the basis of oligomenorrhea, hirsutism, and persistent elevations of urinary 17-ketosteroids and pregnanetriol. She proved resistant to adrenal suppression, and by her later 20s she had become markedly obese (body mass index, 40–44 kg/m2) and progressively hirsute on doses of prednisone equivalent to 24.5 mg/m2 of hydrocortisone (HC). Adrenalectomy was performed because of glucose intolerance believed to be related to her high steroid dosage (9).
Safety of the operative procedure
Thirteen of the patients were adrenalectomized by laparoscopic surgery, and five had traditional flank incisions. No notable operative complications were encountered. The patients who were operated on by laparoscopy had low postoperative morbidity and were discharged from the hospital within 1–4 d.
Responses to adrenal crises and other illnesses
There were no deaths. Five patients had one or more incidents of crisis or other serious illness at some time after surgery, but all responded well to proper therapy.
One of the teenagers (LM) developed afternoon fatigue and had an episode of adrenal crisis from laxness in taking medication. She responded well to regular medications (9).
The 30-yr-old woman (SD) with late-onset CAH lost 13 kg in the first 3 postoperative months, and then she had an adrenal crisis with hyponatremia and hyperkalemia associated with pyelonephritis. She had no further problems after adjustment of her replacement medications (9). She is now maintained on prednisone (5 mg/d) and fludrocortisone (0.2 mg/d). Her obesity and glucose intolerance have persisted.
One of the patients (MC) survived two crises postoperatively. She was poorly compliant and a known drug abuser who had suffered repeated crises before her adrenals were removed. Adrenalectomy had been performed because of a suspected adrenal tumor (10).
Two of the younger patients (AB and ML) had serious illnesses postoperatively. ML was well controlled on a mean HC dose of 20 mg/m2 before adrenalectomy at 8 yr. After adrenalectomy her baseline dose of HC had been reduced to 8 mg/m2. Three months after adrenalectomy, she developed acute gastroenteritis, missed her evening meal, and probably vomited her evening dose of HC. The following morning she was found comatose in bed with severe hypoglycemia. No further episodes of hypoglycemia have occurred after her daily dose of HC was increased from 8 mg/m2 to 12 mg/m2 and the need for increased doses during stress was reemphasized. She has been left, however, with epileptic sequelae that are controlled by appropriate medication. One year after adrenalectomy, she experienced a severe viral pneumonia that needed artificial ventilation and intensive care for 2 wk.
The youngest patient of this series (AB), who was adrenalectomized at 16 months, also had a short episode of hypoglycemia with seizures during an illness in which she had been febrile for 4 d and had fed poorly. At that time her baseline dose of HC was 8 mg/m2. While on the lower doses of HC, she consistently had elevated levels of ACTH and 17-OH-progesterone. Her ACTH and 17-OH-progesterone levels quickly fell when her HC dosages were increased to 11–13 mg/m2 (Fig. 1). She is now a healthy child leading a normal life 6 yr after adrenalectomy.
|
Hyperpigmentation and elevated ACTH levels were observed in more than half of the patients. This was often the result of attempts to reduce HC dosages to 10 mg/m2 or lower. When the dose of HC was increased to 11–13 mg/m2, the serum ACTH levels fell to normal, and pigmentation disappeared. ACTH levels proved to be the most reliable indicator of substitution therapy, because ACTH levels rose to abnormally high levels when the dosage of HC was too low (Fig. 1
).
Significant elevations of steroid precursors were observed postoperatively in eight of the 18 patients. This incidence is probably an underestimate because postoperative steroid levels were not measured systematically in most patients. Presumably these circulating steroids arose from adrenal rests, although in adult women it is difficult to discriminate between adrenal rests in the ovaries and polycystic ovarian disease. Avila et al. (15) found ultrasonic evidence of adrenal rests in 30% of testes in boys with CAH. Ectopic adrenal tissue has also been observed in the broad ligament, along the spermatic cord, and in the celiac plexus (16, 17, 18). Although resumption of virilization from these remnants has the potential of eventually nullifying the beneficial effects of adrenalectomy, resuppression of the adrenals in this series has not proven difficult, and recurrent virilism, if present, has been far less of a problem than before surgery.
Benefits of adrenalectomy
These patients and their parents were nearly unanimous in their enthusiasm for adrenalectomy. In virtually all patients, signs of androgen excess have greatly lessened, and, although obesity has not miraculously disappeared, it has almost uniformly become less of a problem after reduction of the glucocorticoid dosage. Although the effect of adrenalectomy on bone mineral density was not studied in these patients, lowering the dose of HC would be expected to have a beneficial effect. Many of the patients and their families commented on their relief from the need for frequent monitoring.
A 28-yr-old infertile woman with oligomenorrhea resumed menstruation and gave birth to a normal female child (8). Chabre et al. (12) reported excellent results in an XX male with 11ß-hydroxylase deficiency. Although the patient was a genetic female, her external genitalia had been severely masculinized in utero; during early childhood her uterus and ovaries had been removed, and she had been reared as a male. During childhood "he" developed severe hypertension. Adrenalectomy was performed at the age of 44 yr because he had developed hypertensive retinopathy and because medical control of his severe hypertension had become increasingly difficult. Adrenal suppression could not be achieved without producing severe manifestations of hypercortisolism. Now, 4 yr after adrenalectomy, he is normotensive, and he faults his physician for not having removed his adrenals earlier.
The initial patient in this series (LZ), who was 3 yr old at the time of her adrenalectomy, was one of dizygotic twins conceived by in vitro fertilization. We have previously reported that before surgery, exogenous ACTH caused sodium loss in this patient, whereas ACTH caused sodium retention in her normal twin (6). ACTH likewise caused sodium loss in the two children (AB and ML) studied by Ritzen. We attribute this paradoxical response in patients with CAH to the stimulation of adrenal metabolites that act as competitive inhibitors of aldosterone and cortisol at the level of their receptors (19). The adrenals of these three patients were adequately suppressed at the time of the study. Exposure to endogenous ACTH from stress in poorly suppressed patients could have catastrophic consequences.
LZ has thrived in the 6 yr that have elapsed since adrenalectomy. At the time of this report, she is a 9-yr-old fourth-grader living a normal life. Her mother responds quickly with stress doses of HC in response to respiratory infections. She now returns to the endocrine clinic only twice a year, more out of habit than necessity.
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
After adrenalectomy we have found that glucocorticoid therapy can generally be maintained at replacement dosages that are lower than the suppressive dosages that were often required before adrenalectomy. Mineralocorticoid supplementation is mandatory, but dosages rarely need adjustment, and can be easily monitored by infrequent renin measurements. Supplementation with adrenal androgens may be considered at puberty. The need for dehydroepiandrosterone supplementation remains controversial. Further studies will be required to determine the degree of protection provided by adrenals of patients with mutations that permit some residual adrenal function.
Bilateral adrenalectomy removes the adrenal medulla as well as the cortex. This deprives the patient of epinephrine and probably results in reduced ability to respond to stress. It has recently been shown by Merke et al. (20), however, that patients with CAH on glucocorticoid substitution already have greatly reduced secretion of epinephrine. This is explained by the requirement for high local concentrations of glucocorticoid in the adrenal for normal medullary differentiation and the conversion of norepinephrine to epinephrine.
The present studies reinforce the necessity for preventing sustained high levels of ACTH. This is particularly important because many patients have adrenal rests that are capable of response to ACTH. In our patients, ACTH suppression could usually be achieved with HC dosages of 11–13 mg/m2. Most of the patients in this series were on much higher doses of glucocorticoid before surgery. It is difficult to overstate the importance of promptly instituting stress dosages of glucocorticoids at the onset of illnesses.
Summary
We believe that these long-term studies document that bilateral adrenalectomy is a safe and efficacious method of managing patients with severe forms of CAH. It should be considered in patients who have repeatedly escaped from adrenal suppression and who are now suffering from progressive signs of both androgen and glucocorticoid excess. Adrenalectomized patients will require close medical supervision for life because they will remain at risk for serious consequences or death if not given adequate substitution therapy. Prophylactic adrenalectomy of young patients should be limited to academic centers with established research protocols. Most of the patients in this series report a better quality of life without adrenals than had been their experience before adrenalectomy.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Abbreviations: CAH, Congenital adrenal hyperplasia; HC, hydrocortisone.
Received December 26, 2002.
Accepted March 3, 2003.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  A Luczay, D Torok, A Ferenczi, J Majnik, J Solyom, and G. Fekete Potential advantage of N363S glucocorticoid receptor polymorphism in 21-hydroxylase deficiency. Eur. J. Endocrinol., June 1, 2006; 154(6): 859 - 864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Ogilvie, G. Rumsby, T. Kurzawinski, and G. S Conway Outcome of bilateral adrenalectomy in congenital adrenal hyperplasia: one unit's experience. Eur. J. Endocrinol., March 1, 2006; 154(3): 405 - 408. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
