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Original Studies |
Warren Grant Magnuson Clinical Center (D.P.M., S.H.), Developmental Endocrinology Branch (D.P.M., M.F.K., J.V.J., J.F., G.B.C.), National Institute of Child Health and Human Development, and Diagnostic Radiology Department (S.H.), National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Deborah P. Merke, M.D., Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail: merked{at}mail.nih.gov
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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0.05) higher plasma 17-hydroxyprogesterone,
androstenedione, dehydroepiandrosterone, dehydroepiandrosterone
sulfate, and testosterone levels. Despite elevated androgen levels,
children receiving the new treatment regimen had normal linear growth
rate (at 2 yr, 0.1 ± 0.5 SD units), and bone
maturation (at 2 yr, 0.7 ± 0.3 yr bone age/yr chronological age).
No significant adverse effects were observed after 2 yr. We conclude
that the regimen of flutamide, testolactone, reduced hydrocortisone
dose, and fludrocortisone provides effective control of congenital
adrenal hyperplasia with reduced risk of glucocorticoid excess. A long
term study of this new regimen is ongoing. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As an alternative approach to the treatment of CAH, we hypothesized that the clinical effects of excessive androgen and estrogen could be blocked by the combination of an antiandrogen (flutamide) and an inhibitor of androgen to estrogen conversion (testolactone) (2). This approach should prevent excessive androgen effect through receptor blockade and prevent premature epiphyseal maturation by inhibiting the production of estrogen. The rationale for this new treatment approach arose from earlier successful use of spironolactone, an antiandrogen, and testolactone for the treatment of familial male-limited precocious puberty (5, 6). Flutamide was substituted for spironolactone to avoid the mineralocorticoid antagonist activity of spironolactone in mineralocorticoid-treated patients with CAH.
We previously reported better control of linear growth, weight gain, and bone maturation in a short term cross-over study of this new four-drug treatment regimen containing flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone compared to a control regimen of hydrocortisone and fludrocortisone (7). We report here 2 yr of follow-up of a long term randomized parallel study comparing these two treatment regimens.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty-eight children (16 boys and 12 girls; aged 2 4/12 to 11
6/12 yr) with the classic form of 21-hydroxylase were studied (Table 1
). At study entry, there were no
differences between the two arms for age, hydrocortisone dose,
fludrocortisone dose, number receiving GnRH analog treatment, and
midparental height (Table 1). Children in the experimental treatment
arm had, on the average, a greater bone age, height, body mass index,
and recent growth velocity than children in the control arm, but these
differences did not reach statistical significance. Bone age ranged
from 2–13 yr before treatment, and growth rates ranged from 5.5–12.6
cm/yr (-0.4 to 4.5 SD units relative to the normal range
for children of the same age and sex) (8, 9, 10). Patients in secondary
GnRH-dependent precocious puberty were treated with the GnRH agonist
deslorelin
(D-Trp6-Pro9-des-Gly10-GnRH
ethylamide) at the dose of 4 µg/kg·day, sc (11). Three patients
were treated with deslorelin for at least 3 months before study entry,
and 3 patients developed secondary GnRH-dependent precocious puberty
after study entry and were subsequently treated with deslorelin. Two
patients (1 in each treatment arm) dropped out of the study after 1.5
yr for social reasons unrelated to treatment.
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The protocol was approved by the institutional review board of the NICHD and by the FDA. Informed consent was obtained from a parent of each patient, and assent was obtained from the older children. At least 3 months before randomization, all children were switched from their previous glucocorticoid formulation to the liquid hydrocortisone formulation (Cortef, Pharmacia & Upjohn, Kalamazoo, MI; 10 mg/mL) that was used throughout the study. While administering hydrocortisone, the mineralocorticoid dose of the 21-hydroxylase-deficient patients was adjusted to maintain normal PRA. Pretreatment growth velocity was determined over an interval of 3–12 months.
Children were randomized to receive either flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone or a regimen of hydrocortisone and fludrocortisone. Adjustments in total hydrocortisone dose per m2 body surface area were made as clinically indicated for children in the hydrocortisone and fludrocortisone treatment arm. For children randomized to the new treatment regimen, flutamide and testolactone were incrementally increased, whereas the dose of hydrocortisone was gradually decreased in a stepwise fashion over 3 weeks (7). The majority of children were decreased to a hydrocortisone dose of 8 mg/m2·day (in two divided doses); however, adjustments of hydrocortisone dose in the flutamide and testolactone arms were permitted. One child with difficult to control hyperandrogenism before study entry was decreased to a hydrocortisone dose of 12 mg/m2·day. The hydrocortisone dose was decreased to 6 mg/m2·day in one child. Because of our concerns that very high androgen levels may have the potential to overcome the beneficial effects of flutamide, and very high ACTH levels may increase adrenal rest tissue formation, the hydrocortisone dose was generally increased for children receiving the new treatment regimen if 2 or more of the following occurred: the rate of bone age advancement was greater than 2 yr/chronological yr without evidence of central precocious puberty as the cause, plasma 17-hydroxyprogesterone levels were above 10,000 ng/dL (300 nmol/L), plasma androstenedione levels were above 500 ng/dL (17.5 nmol/L), or testosterone levels were above 100 ng/dL (3.5 nmol/L) in girls or prepubertal boys. The hydrocortisone dose was also increased if there was clinically detectable testicular adrenal rest tissue. The hydrocortisone dose was generally decreased for 17-hydroxyprogesterone levels below 500 ng/dL (15.1 nmol/L), androstenedione levels below 50 ng/dL (1.7 nmol/L), or weight percentile greater than height percentile. In this long term study, testolactone will be discontinued at age 13 yr in girls, and both testolactone and flutamide will be discontinued at age 14 yr in boys to allow puberty to progress. In girls, flutamide will be continued throughout puberty.
Children were evaluated at 6-month intervals with the following measures: the mean of 10 height measurements by stadiometer, weight, pubertal stage (12, 13), testicular ultrasound (to detect adrenal rest tissue), and 3 measurements at 20-min intervals starting at 0800 h of plasma ACTH, 17-hydroxyprogresterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone, and estradiol. The morning hydrocortisone dose was withheld until after these samples were obtained.
The rationale for this sampling protocol, which has been used in this clinic for many years, was to reduce variability due to circadian variation, hormone pulsatility, and the acute effects of the morning hydrocortisone dose. This protocol yields higher adrenal androgen levels than typical out-patient measurements. Early morning premedication adrenal androgen levels are approximately 3-fold higher than measurements obtained later in the day and after taking the morning hydrocortisone dose.
Supine and upright PRA, electrolytes, complete blood count, and hepatic and renal functions were also measured. Urine was collected over 24 h for 2–3 consecutive days for determination of free cortisol. Gonadotropin levels were measured at the time of 100 µg iv injection of GnRH, and at 15, 30, 45, 60, and 90 min thereafter for evaluation of secondary central precocious puberty (14). Bone age was determined from a radiograph of the left hand and wrist (15) by a single radiologist who was unaware of the patient’s treatment status. Between visits, at 3-month intervals, plasma 17-hydroxyprogesterone, androstenedione, ACTH, testosterone, estradiol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and renin activity were measured.
A rare side effect of flutamide is hepatotoxicity, which is reversible with prompt cessation of the drug and typically occurs within the first 7 months of therapy (16, 17). Parents of children randomized to receive flutamide were educated about signs and symptoms of liver toxicity (anorexia, nausea, vomiting, diarrhea, malaise, fatigue, dark urine, or jaundice). Liver function studies were monitored every 2 weeks for the initial 3 months, every month for the subsequent 9 months, and every 3 months thereafter. Parents were instructed to discontinue the drug and have liver function tested if any symptoms or signs of liver toxicity occurred.
Hormonal measurements
Plasma 17-hydroxyprogesterone, androstenedione, ACTH, testosterone, estradiol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, LH, and FSH were measured by RIA as previously described (7). All measurements were performed by Hazelton Laboratories (Vienna, VA). Urinary free cortisol measurements were adjusted by body surface area (18).
Statistical analysis
Statistical analyses were performed using the Statistical
Analysis System (version 6.12, SAS Institute, Inc., Cary,
NC). The mixed procedure was used to fit a linear model for repeated
measures and to examine time and treatment effects on growth, bone
maturation, weight, and hormonal data. Differences at baseline and
other time points were derived from the model. Values were expressed as
the arithmetic mean ± SEM unless otherwise specified.
The level of significance was taken as P 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The reduction of hydrocortisone dose during flutamide and testolactone
treatment caused the expected increase in plasma
17-hydroxyprogesterone, androstenedione, testosterone,
dehydroepiandrosterone, and dehydroepiandrosterone sulfate (Fig. 1). There were no significant trends in
hormone levels over time. After 2 yr of therapy, plasma ACTH was also
higher in the flutamide and testolactone treatment group [283 ±
66 pg/mL (62.9 ± 14.7 pmol/L) vs. 180 ± 70 pg/mL
(40 ± 15.5 pmol/L)], although the difference did not achieve
statistical significance. There was no significant difference in levels
of estradiol between the two groups. Most levels of estradiol were at
or below the detection limit of our assay. The urinary free cortisol
level was lower in the patients receiving the four-drug regimen
[average, 17.6 ± 3.9 µg/m2·day
(48.6 ± 10.7 nmol/m2·day) vs.
20.6 ± 4.1 µg/m2·day (56.8 ± 11.3
nmol/m2·day)], but this difference did not
reach statistical significance.
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). Compared to the two-drug regimen
arm, significant (P 0.01) differences in growth were
observed over time. Thus, despite increased androgen levels, the
regimen containing flutamide and testolactone produced slower growth
rates that were appropriate for the patient’s chronological age.
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0.01) in the children receiving the regimen with flutamide and
testolactone (Fig. 2B
). Children receiving the four-drug regimen had,
on the average, an increase in predicted height (from -2.6 ± 0.5
to -2.0 ± 0.5 SD units; P
= 0.30), but this difference did not reach statistical significance.
The rate of weight gain declined during the first 6 months of treatment
for patients on the four-drug regimen [from 2.2 ± 0.8 kg/yr
(0.4 ± 0.7 SD units) to 1.8 ± 0.8 kg/yr (-0.2 ± 0.7
SD units)], but there were no significant
differences in weight velocity or body mass index between the two
treatment arms.
At 2 yr of follow-up, four children in the experimental treatment arm
and two children in the control arm were receiving deslorelin therapy
(P = 0.6). When these six children were omitted from
the data analysis, growth velocity and bone age maturation normalized
in both groups at 2 yr (control: 1.3 ± 0.5
SD units, 1.2 ± 0.7 yr bone age/yr
chronological age; experimental: 0.1 ± 0.5
SD units, 0.7 ± 0.2 yr bone age/yr
chronological age; Fig. 2, C and D). Although the children on the
two-drug regimen still had higher rates of growth and bone maturation,
the differences between the two subgroups who remained prepubertal at
the 2-yr point did not achieve statistical significance. Restricting
the analysis to the prepubertal children did not alter the hormonal
findings. Plasma 17-hydroxyprogesterone, androstenedione,
dehydroepiandrosterone, dehydroepiandrosterone sulfate, and
testosterone remained significantly (P < 0.05) higher
in the children receiving the four-drug regimen (data not shown).
Similarly, plasma ACTH was higher and urinary free cortisol was lower
in these patients, but these differences did not reach statistical
significance. Thus, despite significantly increased androgen levels,
children receiving the four-drug regimen had normal growth and bone age
maturation at 2 yr of follow-up.
Adverse effects
No abnormalities in electrolyte, hepatic, renal, or hematological function were observed during either treatment arm. Two patients experienced transient abdominal discomfort and nausea during the first week of flutamide, testolactone, and reduced hydrocortisone dose that resolved spontaneously without any dosage alterations. One patient experienced abdominal discomfort and nausea that did not resolve despite dose adjustments. After 1 month, flutamide and testolactone were discontinued, and the patient was subsequently treated with hydrocortisone and fludrocortisone. Adrenal insufficiency was not observed in any child receiving a reduced hydrocortisone dose. Testicular adrenal rest tissue was detected by a screening ultrasound in four boys, two in each arm. Three of the four boys had small (1–2 mm) testicular adrenal rests, which disappeared without a change in therapy. One boy receiving flutamide, testolactone and reduced hydrocortisone developed significant bilateral testicular adrenal rest tissue (right, 1.0 x 0.9 x 1.8 cm; left, 1.2 x 1.2 x 1.4 cm). The testicular adrenal rest tissue decreased with an increase in hydrocortisone dose. He is currently receiving flutamide, testolactone, 16 mg/m2·day hydrocortisone, and fludrocortisone.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Hydrocortisone doses were significantly lower in the experimental arm, but were also tailored to individual differences in glucocorticoid requirement. A hydrocortisone dose of 8 mg/m2·day was chosen in our initial pilot study based on estimates of normal production rate (19); however, children may vary in their glucocorticoid daily requirements. CAH occurs in several clinically distinct variants that reflect differing severity of the underlying enzymatic deficiency. Even within the salt-wasting and simple virilizer subgroups of classic CAH, clinical heterogeneity is seen (20, 21). This may be due to varying genotypes, heterogeneity of glucocorticoid metabolism or sensitivity, or other unknown factors. Thus, although glucocorticoid doses were generally decreased to physiological levels in the group receiving flutamide and testolactone, hydrocortisone doses were not identical for all children receiving the four-drug regimen. Development of clinically detectable testicular adrenal rest tissue, which occurs in a minority of boys with CAH, should be treated with higher doses of glucocorticoid to prevent further enlargement of adrenal rests. Children receiving lower dose hydrocortisone had slightly higher fludrocortisone doses. Although this fludrocortisone dose increase and the difference between treatment arms were not significant, the intrinsic glucocorticoid activity of this slightly higher fludrocortisone dose would be predicted to have compensated for 8% of the reduction in hydrocortisone dose.
In our short term cross-over pilot study (7), plasma androstenedione and testosterone levels did not increase as a result of the hydrocortisone dose reduction during flutamide and testolactone treatment. Thus, the levels of these steroids were discordant from those of their precursor, 17-hydroxyprogesterone, which increased more than 3-fold. In our current study we observed increases in testosterone and all of its precursors. One possible explanation for these different observations is the greater age of patients in the current study. At study entry, 8 of 12 (66.7%) children had a bone age less than 5 yr in our pilot study, whereas only 9 of 28 (32.1%) had a bone age less than 5 yr in our current study. A maturational increase in 17–20-lyase activity occurs as children reach adrenarche (22, 23). This age-associated difference in 17–20-lyase activity most likely explains the difference in androstenedione and testosterone levels between the two studies.
Unexpectedly, plasma corticotropin levels were not significantly higher in the patients who received a reduced hydrocortisone dose. Dissociation between plasma adrenal androgens and cortisol secretion has been observed (24), suggesting that a factor other than corticotropin may stimulate adrenal androgen secretion. Alternatively, our method of sampling (at 0800 h, 12 h after the last medications) may have missed the early morning corticotropin peak.
Our observation of growth rate and bone maturation that were above the median normal value for age despite treatment with hydrocortisone and fludrocortisone may be due to several factors. Many patients were referred to our center because of difficult to control hyperandrogenism and had been treated with high doses of glucocorticoid. We attempted to reduce hydrocortisone to the lowest effective dose, even in the hydrocortisone and fludrocortisone arm; consequently, the most common change made in therapy upon referral was a decrease in hydrocortisone dose. Although an increased hydrocortisone dose could have achieved greater suppression of growth velocity and bone maturation, such a dose change would have increased weight gain. Our effort to reduce hydrocortisone dose to the lowest effective dose, even in the control arm, is the most likely explanation for the lack of significant difference in body mass index and weight velocity between the two arms.
We recognize that the management of our control arm may differ from that of other pediatric endocrinologists. To minimize supraphysiological glucocorticoid dosage, 17-hydroxyprogesterone levels were allowed to remain elevated. Despite the effort to reduce hydrocortisone to the lowest effective dose in the control arm, the dose of hydrocortisone used was approximately twice the normal childhood production rate (13.3 ± 0.6 vs. 6.8 ± 1.9 mg/m2·day) (19). It is our judgement that much of the short stature observed in children with CAH is due to supraphysiological glucocorticoid treatment. A previous effort to correlate the degree of biochemical control with adult height has shown no correlation (25), which we have interpreted as reflecting loss of height potential due primarily to sex steroid excess in the poorly controlled subjects and to glucocorticoid excess in the apparently well controlled subjects (2, 3, 6). The ideal treatment approach is unknown. There may be research strategies that could improve the outcome of hydrocortisone and fludrocortisone treatment; however, we emphasize that the regimen containing flutamide and testolactone and reduced hydrocortisone dose fully normalized both growth rate and bone maturation for the 2-yr duration of these observations despite increased androgen levels.
This clinical trial tests a new treatment strategy consisting of an antiandrogen, an aromatase inhibitor, and reduced hydrocortisone dose in the treatment of CAH. Flutamide and testolactone were chosen because of our prior experience with these drugs. Although no liver toxicity has been observed in the subjects in this study, considerable vigilance is required to use flutamide safely in children, and safer antiandrogens are needed. We did not encounter problems with compliance; however, the use of a longer acting antiandrogen and aromatase inhibitor would simplify this approach.
Existing treatment has often failed to normalize the growth and development of children with CAH. The use of adrenalectomy as a treatment option for CAH has been proposed recently for severely affected children in whom it is difficult to maintain satisfactory adrenal suppression without producing hypercortisolism (26, 27). Our current study tests an alternative medical approach. The preliminary results are promising. The children receiving reduced hydrocortisone, an antiandrogen, and an aromatase inhibitor maintained normal growth velocity and bone maturation despite significantly elevated androgen levels. However, the ultimate test of this treatment is whether it can maintain normal growth and development throughout childhood and adolescence. Until longer term results are available, use of this new approach outside of an investigational setting would be premature.
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Acknowledgments |
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Footnotes |
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2 Present address: Eli Lilly & Co., Lilly Research
Laboratories, Indianapolis, Indiana 46285.
Received March 25, 1999.
Revised August 30, 1999.
Revised November 4, 1999.
Accepted November 29, 1999.
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References |
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) compared to those
in children treated with hydrocortisone (13.3 ± 0.6
mg/m2·day) and fludrocortisone (
). Values are the
mean ± SEM. The asterisk indicates a
significant difference (P < 0.05) between the two
groups at 2 yr by repeated measures analysis.
)
received hydrocortisone and fludrocortisone. A and B include all
subjects; C and D show children who remained prepubertal at 2 yr and
exclude the six children who were receiving GnRH analog. Values are the
mean ± SEM. The asterisk indicates a
significant difference (P < 0.05) between the two
groups by repeated measures analysis.