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Original Studies |
Genentech, Inc., San Francisco, California 94080
Address all correspondence and requests for reprints to: Dr. Steven D. Chernausek, Children’s Hospital Medical Center, Division of Endocrinology, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The hypogonadism of Turner syndrome has also been exploited in the effort to augment stature. Because most patients will not enter puberty without sex steroid therapy, the initiation of puberty is typically delayed beyond age 14 yr to prolong the growing period and thereby increase adult height. This is usually done independently of whether the patient receives other growth-promoting therapy. However, the beneficial effect of this approach has not been adequately quantified, especially in patients who are concomitantly treated with GH. Sex steroid therapy initially accelerates growth; however, adult height data are necessary to determine whether this compensates for the height lost due to accelerated skeletal maturation and earlier epiphyseal fusion. Moreover, there may be psychological and social penalties in delaying puberty in these patients already stigmatized by short stature and dysmorphic features.
The questions surrounding the effects of estrogen therapy in the background of GH treatment led us to prospectively examine the impact of timing of feminization in patients with Turner syndrome. The patients were involved in a multicenter trial of GH therapy that has not been previously reported other than in a preliminary form (10, 11). Two cohorts of patients were defined on the basis of chronological age at initiation of GH therapy. Younger patients (<11 yr at start of GH therapy) were randomized to begin a feminization regimen with conjugated estrogens at either 12 or 15 yr of age and were examined periodically until near final height was achieved. The remainder received estrogens after 1 yr of GH therapy. We now report the effect of estrogen therapy on bone maturation, rate of feminization, and growth velocity as well as the impact that age at pubertal initiation has on adult height in patients treated with GH.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty-one medical centers enrolled 117 patients between the ages of 8 and 16.4 yr during 1987 and 1988. The diagnosis of Turner syndrome was confirmed by karyotype. Both 45,XO and variants of X-chromosome abnormalities (e.g. partial deletions, mosaics) were included, but no patients displaying Y-chromosome material on karyotype were allowed. All patients were at least 1 SD below the mean height for chronological age of normal females by the National Center for Health Statistics standards (12) and had pretreatment growth rates of less then 6 cm/yr. All patients were required to show a normal peak GH response (>7 µg/L) by any GH stimulation test. Patients with diabetes mellitus or previous growth-promoting therapy were excluded, as well as those with malignancy or other systemic illness. All protocols were reviewed and approved by the institutional review boards at each center, and a written form was used to document informed consent.
Treatment protocol
All patients received GH for at least 1 yr before beginning estrogen therapy. Those less than 11 yr of age at entry (n = 60) were randomized to begin estrogen therapy at either 12 or 15 yr of age (n = 30 in each group). Patients more than 11 yr old at entry (n = 57) received 1 yr of GH, after which estrogen therapy was begun. Nearly all patients adhered to these aspects of the protocol, but in a few cases the timing of estrogen initiation was altered because of patient/physician decision (see Results). An additional goal of the study was to compare the efficacy of daily vs. three times weekly GH injections; thus, all patients were randomly assigned to receive either dose regimen. The groups were balanced with respect to age, growth rate during the first year of GH therapy, and frequency of GH administration. Recombinant human GH (somatropin, Nutropin, Genentech, Inc., San Francisco, CA) was given by sc injection at a dose of 0.375 mg/kg·wk. Treatment with GH was continued until the bone age was greater than or equal to 14 yr and the growth rate was less than 2.5 cm/yr.
Estrogen replacement was given as conjugated estrogens (Premarin, Wyeth-Ayerst Pharmaceuticals, Inc., Philadelphia, PA) at a dose of 0.3 mg daily for 6 months, after which the dose was increased to 0.625 mg daily. After 1 yr of estrogen therapy, patients received 10 mg medroxyprogesterone acetate (Provera, Upjohn, Kalamazoo, MI) for 10 days each month to induce regular menstrual cycles. All patients were monitored at their participating center at least every 6 months. Procedures performed at clinic visits included a complete physical examination, assessment of pubertal stage, complete blood count, serum chemistry panel, urinalysis, fasting and postprandial glucose and insulin measurements, thyroid function tests, and measurements of antibodies to GH.
Outcome variables
Standing height was the mean of three separate measures using a Harpenden stadiometer or an equivalent wall-mounted device. Bone age was obtained from a hand/wrist radiograph read by a single observer, blinded to patient group assignment, at the Fels Research Institute (Yellow Springs, OH). Pubertal stage was assessed by the method of Tanner (13). Final (or near final) height was defined as last measured height after the age of 13.5 yr. This age was selected to maximize the number of patients for analysis even though some patients assuredly had the potential for additional growth. Height gained as a consequence of therapy was determined by subtracting the pretreatment projected adult height from the recorded final height. The projected height [as described previously (14)] predicts growth based on growth curves published by Lyon et al. (2) of untreated patients with Turner syndrome. For the present analysis, the pretreatment projected adult height used the Lyon et al. data and was computed by assuming that without treatment the patient would have had the same Turner standardized height3 at adulthood that she had at baseline (pretreatment). This method has been shown to be accurate with independent U.S. data (15).
Historical controls
Control data were derived from a database of over 1300 American
Turner syndrome patients never treated with GH or androgens (15). Our
patient group had a mean height at baseline identical to that of the
historical reference population, indicating that they were similar in
their growth characteristics. Age-matched controls with both childhood
and adult heights recorded were sought for comparison with the
treatment groups. Of the 1300, 56 had childhood heights determined at
5–16 yr of age as well as adult heights recorded. These patients were
largely reported from the investigational sites participating in other
GH trials. From this latter group, 14 control patients could be matched
by age to the early GH treatment group, and 55 were suitably matched to
the later GH treatment cohort. The mean age for initiation of estrogen
replacement for the matched historical control patients was similar to
or later than that of the delayed estrogen group (Table 1
).
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Baseline characteristics were compared between treatment groups using either Student’s t test or Fisher’s exact test for frequency tables. The most recent heights of the groups randomized to receive estrogen at age 12 or 15 yr as well as those who began GH after age 11 yr were compared with historical controls using analysis of covariance where the covariates were baseline age, baseline height, baseline bone age, karyotype, and midparental target height.
Multiple regression analysis was performed to examine the factors that might contribute to the variability in clinical response to GH. Only variables with statistically significant coefficients (P < 0.01) were retained in the regression equation. In cases where the baseline bone age was missing (n = 4), the baseline bone age was estimated by subtracting the time elapsed between baseline and the first available bone age.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The rate of progression through Tanner stages for breast
development was no different in those patients who began estrogen at
age 12 yr and those who began at age 15 yr. Therefore, the groups were
combined, and the rate of breast maturation after initiation of the
estrogen therapy is displayed in Fig. 1.
The rate of progression through the Tanner breast stages approximates
that reported for normal girls (13).
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GH stimulated linear growth in nearly all patients. The average pretreatment growth velocity was 3.9 ± 1.0 cm/yr. The mean first year growth rate of patients receiving daily GH was 8.1 ± 1.6 cm/yr compared with 6.7 ± 1.5 cm/yr for those treated with GH three times per week (P < 0.001 between dosing frequencies). There was no statistically significant difference between patients receiving daily and three times weekly injections for growth rate after the first year of treatment or for adult height. There was no difference in total duration of GH treatment between the daily and three times weekly groups.
Effect of timing of estrogen therapy on growth and bone maturation in the younger cohort
Baseline characteristics (Table 1
). The average age at
enrollment was 9.5 ± 1.0 yr for the 60 patients randomized to
begin estrogen at either 12 or 15 yr. There were no significant
differences between the 2 treated groups with respect to baseline
height, midparental height, proportion of patients bearing monosomy
45,X, or bone age. Five of the randomized patients were excluded from
the primary analysis for the following reasons: 3 patients assigned to
receive estrogen at age 12 yr in fact did not receive treatment until
after age 14 yr, and 2 patients (1 in each group) had no recorded
height after age 13.5 yr.
Growth rate and skeletal maturation. The mean growth rates for
chronological age of the patients randomized to begin estrogen at
either age 12 or 15 yr are displayed in Fig. 2. Those patients beginning estrogen at
age 12 yr grew, on the average, about 1 cm/yr faster than patients
maintained on GH alone during their first year. However, during the
second year of estrogen therapy, their growth rate matched that of
patients who had not yet received estrogen. Subsequently, their mean
growth rate declined even further and fell below that expected in girls
with Turner syndrome given no growth-promoting therapy (2). In
contrast, the average growth rate of patients in whom estrogen was
delayed until age 15 yr was greater than that predicted throughout the
age span.
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). As
expected, the change in bone age per chronological yr was significantly
greater in the earlier treated estrogen group (P =
0.004). Specifically, the bone age advanced, on the average, 3.5 yr
between the ages of 12 and 15 yr for those who began estrogen at age 12
yr compared to only 2.5 yr for the aged-matched group receiving GH
alone. This advancement in skeletal maturation would appear to explain
the decline in growth rate observed after the first year of estrogen
treatment in the patients given estrogen since 12 yr of age.
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). The mean duration of GH therapy was
close to 6 yr in both treated groups. Patients receiving estrogen
beginning at age 12 ys were, on the average, 5.1 cm taller than their
pretreatment projected height, whereas the apparent height gain was 8.4
cm in those patients in whom estrogen therapy was delayed until age 15
yr, for a mean difference of 3.3 cm (by analysis of covariance,
P = 0.003). The results were similar when height gain
was computed using the matched historical control group for reference
(Table 2). Because control subjects were required to have a height
measured after 18 yr of age whereas treated subjects were only required
to have a height measured after age 13.5 yr, the calculated gain in
height of treated subjects was conservative; this is particularly true
for the late estrogen recipients, who sustained less advancement of
bone age. Data for individual patients show that there was significant
overlap among the groups despite a clear difference between group means
(Fig. 4). This individual variability
probably reflects the imprecision of final height prediction rather
than a variable response to GH treatment, because the variability among
the untreated patients was substantive as well.
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Patients over age 11 yr when GH therapy was initiated all began
estrogen therapy after 1 yr of GH treatment and received GH for an
average of 3.8 yr. Six patients did not receive more than 1 yr of GH
and were, therefore, excluded from the analysis. The mean near final
height of this nonrandomized group (n = 51; 148.5 cm) resulted in
a mean adult height gain of approximately 5 cm, similar to that of the
group that began estrogen at age 12 yr. Height gains of individuals are
shown in Fig. 4.
Factors predicting response to therapy
The impacts of age, height, and bone age at baseline along with karyotype, midparental height, age at last measured height, and duration of GH therapy before introduction of estrogen were assessed. The analysis was performed on those patients in the younger cohort who had a height measured after age 13.5 yr (n = 58), using the last measured height minus the Lyon projected adult height at baseline (i.e. height gain) as the dependent variable. Significant predictive factors were baseline age, baseline bone age, age at last measured height, and GH therapy duration before estrogen (P < 0.01 for each). The overall r2 was 51%.
The apparent significant impact of age at last measured height suggested that the cohort described above had not yet reached final height. Thus, an additional analysis was performed that was restricted to subjects with last measured height at age 16 yr or later (n = 29) to be more certain that growth was reasonably complete. The resulting multiple regression analysis contained only the number of years of GH treatment before estrogen therapy as a significant factor (P < 0.0001; r2 = 41%). The equation was simply: height gain (cm) = 2.1 x yr of GH therapy before estrogen treatment.
Adverse events
Several detrimental conditions have been previously reported to occur in association with GH therapy, including slipped capital femoral epiphysis, carpal tunnel syndrome, idiopathic intracranial hypertension, and pancreatitis (16). None of these occurred in patients in this study. There were two serious adverse events noted, however. One patient was diagnosed with a cerebrovascular accident when progressive symptoms of right-sided weakness and slurred speech were reported. The patient had been receiving GH therapy along with estrogen and medroxyprogesterone acetate. Evaluation demonstrated a unilateral ischemic stroke in the lenticulostriate area of the brain. GH and sex steroid therapy were discontinued, and the incident was considered by the investigator to be unrelated to GH therapy, but possibly related to Turner syndrome and/or sex steroid therapy. One patient developed hypoplastic anemia while receiving anticonvulsive therapy and antihypertensive therapy along with GH. The investigator believed that the anemia was due to anticonvulsive therapy and stopped all medications except GH and estrogen. Her hemoglobin and hematocrit remained stable over the next several clinic visits.
A single patient developed an allergy to the excipient used with the GH preparation. No patient developed clinically significant glucose intolerance, nor was there any evidence that the early estrogen induction had any effect on inducing glucose intolerance. There was also no difference in blood pressure between the early estrogen and late estrogen groups. Although there were other adverse events reported as severe (e.g. syncope with fever, migraine, and otitis), none was attributed to the study drug by investigators.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We examined the impact of estrogen therapy on growth and feminization in Turner syndrome girls receiving GH and have shown that the age at which estrogen therapy is initiated has a significant influence on the adult height achieved. This is based on the analysis of a group of GH-treated patients randomly assigned to begin estrogen therapy at either 12 or 15 yr of age. When GH therapy is begun at an average age of 9.5 yr, and estrogen is withheld until after age 15 yr, there is an apparent net gain of 8.4 cm in final height; this is identical to that previously reported by our investigator group for a distinct set of patients treated similarly (9). In contrast, the matched group given estrogen therapy at 12 yr gained only 5.1 cm.
Although the combination of estrogen with GH initially stimulates growth velocity above that observed with GH alone, this is accompanied by accelerated bone maturation, and the growth rate subsequently declines. Indeed, after 2 yr of estrogen therapy the growth rate slows to less than that expected for untreated patients. The net effect is such that deferring estrogen therapy for 3 yr (i.e. from age 12 to 15 yr) produces an additional gain of at least 3.4 cm (based on analysis of covariance) in adult height, on the average. It should be emphasized that the reported height gains are probably underestimates, because physeal closure was incomplete in many of the girls at the time of last measurement, and the underestimation may have been greater in those in whom estrogen therapy was delayed until age 15 yr. The degree of underestimation, however, is difficult to quantify.
The widely prescribed feminization regimen we chose produced an
apparently normal rate of breast development in the majority of
patients regardless of the age at which it was initiated. Although
final height is diminished when estrogen therapy is introduced at an
age that approximates normal puberty, it has been suggested that a
lower dose of estrogen might permit more growth during feminization. An
earlier study by our investigator group demonstrated that combining
oxandrolone with GH causes a sustained increase in growth velocity
above that observed with GH alone, and although bone maturation is
accelerated, final height is not reduced (9). Thus, it is logical to
postulate that a lower dose of estrogen might have a similar
synergistic or additive effect during GH therapy. This idea was
seemingly supported by the studies of Ross et al. (22),
which showed that low dose ethinyl estradiol alone
stimulated short-term growth in patients with Turner syndrome without
excessive bone age advancement. Despite this, later reports examining
estrogen and GH in combination were not encouraging and were generally
limited to short-term (1- to 2-yr) studies that examined the effect of
GH with or without estrogen on growth rate, bone age advancement, and
feminization. Vanderschueren-Lodeweyckx et al. (23)
administered 25 ng/kg ethinyl estradiol daily in
combination with GH. The increase in growth from estradiol was minimal,
and even this very low estrogen dose induced breast development and
accelerated bone maturation. Job et al. (24) performed a
similar study and found that estradiol increased the first year growth
rate in girls with Turner syndrome when given with GH at a dose of 0.45
IU (
0.15 mg)/kg·wk, but not when given with a higher dose of GH.
Similarly, they found that bone maturation accelerated and suggested
that giving estradiol with GH in the prepubertal age range should be
avoided. More recently, Nilsson et al. (17) reported final
height of Turner syndrome patients given GH and oxandrolone with or
without the addition of 100 ng/kg·day ethinyl estradiol.
Here again, estrogen therapy appeared to reduce the gain in height
achieved by the growth-promoting agents.
Recent reports reiterate that the dominant effect of estrogens on bone is the enhancement of bone mineralization and epiphyseal maturation, with a lesser influence on growth promotion. Smith et al. (25) described a male with estrogen resistance due to an estrogen receptor mutation who reached supranormal stature and maintained open epiphyses for many years in the presence of normal adult male levels of testosterone. Furthermore, a preliminary report indicates that adult stature can be augmented when puberty is delayed by GnRH analog administration in patients with idiopathic short stature (26). Thus, although we cannot exclude the possibility that a lower dose of estrogen might yield less growth attenuation and still provide the desired effects of feminization, there are few data supporting this idea. Because a fixed dose of estrogen was used, our study cannot address this issue.
Our data strongly suggest that the age at which GH therapy is initiated is also an important determinant of the ultimate response. Indeed, the multivariate analysis we performed indicated that the duration of GH therapy before estrogen initiation was the single most important factor in predicting the response to therapy. Nearly all prior reports that show relatively modest gains in height have studied patients who began GH at ages more advanced than our younger cohort, often with estrogen therapy introduced shortly thereafter. For example, the 3-cm net gain in height reported by Van den Broeck et al. (8) was in patients beginning GH at an average age of nearly 13 yr who received estrogen therapy soon thereafter at a mean age of 14.5 yr. The use of Ranke projected adult height [which may overestimate adult height (27)] in this study may have led to an underestimate of net gain. Similarly, the patients described by Taback et al. (20), the majority of whom they reported to have gained less than 5 cm, began GH at 12 yr and started estrogen only 1.3 yr later, on the average. The data we report in our older cohort are, in fact, quite consistent with these other reports. This nonrandomized group in our study who were older at GH initiation (mean, 12.7 yr) and who began estrogen after only 1 yr of GH therapy gained, on the average, only 4.7 cm. Based on these data, we believe that the modest gains in adult height reported by some reflect at least in part relatively early estrogen treatment of patients given GH at somewhat advanced ages. When all of these factors are considered, the reported literature seems consistent with our observation that patients who receive estrogen early relative to GH initiation fare less well in terms of adult stature.
The information provided by our study should be useful for clinicians treating patients with Turner syndrome. It appears that GH is safe and increases adult height with or without concomitant estrogen therapy. In general, one can expect approximately 2 yr of continued growth after the initiation of estrogen using the regimen described. Although the patients with the greatest gains in adult height were those that began estrogen therapy after the age of 15 yr, the message of this report is not necessarily that estrogen replacement should be deferred as long as possible, as this may have adverse effects on the patient’s psychosocial development as well as her bone mineral status (28). Rather, therapeutic regimens that will bring the patients into the normal range for height at pubertal age should be sought. This should allow an earlier introduction of estrogens and an acceptable final height. This might be achieved by introducing GH earlier than the mean age of 9.5 yr in the younger cohort, by using higher doses of GH [as was recently demonstrated by Sas et. al (29)], or perhaps by combining GH with oxandrolone to produce more rapid growth during the initial years of therapy (14). This new information describing the growth and maturation effects of GH and estrogens will not only allow physicians to more accurately gauge the optimal timing of estrogen initiation for each individual with Turner syndrome, but will also be useful to patients and families as they weigh the expected outcomes of various therapeutic alternatives.
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Footnotes |
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2 The Genentech, Inc., Collaborative Group for this
study consisted of the following investigators: G. August, D. Bier, S.
Blethen, R. Blizzard, D. Brown, S. Burstein, J. Cara, S.
Chernausek, T. Foley, M. Geffner, R. Gotlin, R. Hintz, A. Hollander, S.
LaFranchi, B. Lippe, M. MacGillivray, P. Mahoney, L. Plotnick, A.
Rogol, R. Rosenfeld, R. Rosenfield, K. Rubin, P. Saenger, J.
Sockalosky, and D. Styne. The following persons from Genentech, Inc. also contributed to the study: L. Brelsford, D. Brown, L.
Frahm, J. Kuntze, A. Johanson, K. Nemo, A. Perlman, B. Sherman, and P.
Martha.
3 Turner standardized height is observed height
minus Turner mean expected height for age divided by the standard
deviation of the height for age.
Received March 9, 2000.
Revised April 13, 2000.
Accepted April 13, 2000.
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