Clinical Endocrinology (2006) 64, 423–428
Effects of growth reduction therapy using high-dose
β-estradiol in 26 constitutionally tall girls
U. Radivojevic, E. Thibaud, D. Samara-Boustani, C. Duflos and M. Polak Department of Paediatric Endocrinology and Gynaecology, Necker-Enfants Malades Hospital, Paris, France Introduction
The use of sex steroids to reduce final height in patients with con- Objective The efficacy and safety of height-limiting therapy with
stitutionally tall stature (CTS) remains controversial. CTS is defined high-dose 17β-oestradiol in girls with constitutionally tall stature as an SD of at least 2 above the mean height for sex and chronological (CTS) are controversial. We evaluated the effectiveness of high-dose age in a relevant reference population,1 after exclusion of overgrowth 17β-oestradiol in premenarchal girls with CTS treated until their syndromes.1–3 Although CTS is related primarily to familial factors, nutrition,1,2 hormonal status and socioeconomic environment also Design We retrospectively reviewed the medical records of the girls
managed between 1989 and 2000 with high-dose 17β-estradiol for The diagnosis usually rests on a family history of tall stature and on CTS with a predicted final height greater than +3SDs.
physical findings distinguishing CTS from overgrowth syndromes.1–3 Patients Twenty-six girls met our inclusion criteria. At baseline, mean
Evaluation of the tall girl should include a medical history, physical chronological age was 12·06 ± 1·51 years and mean height was 171·1 examination, estimation of growth potential and a battery of labor- ± 6·5 cm with a height standard deviation score of 4·5 ± 0·24, and mean predicted final height was 183·0 ± 4·2 cm. Treatment was stopped Bone growth and maturation result from a complex interplay of when bone age reached 14 years; mean treatment duration was multiple hormones and growth factors.1,4 At puberty, sex steroids, predominantly oestrogens in girls (in combination with other hormones Measurements The following were obtained at 6-month intervals:
and growth factors), induce an increase in growth velocity followed height, body weight, Tanner stage, bone age, plasma cholesterol and by closure of the epiphyseal growth plates with cessation of linear triglycerides, plasma glucose and side effects. A mailed questionnaire growth in long bones.4 High-dose oestrogens may accelerate growth plate on final height and satisfaction was sent 2 years after treatment dis- closure without increasing growth velocity, thus reducing the final height continuation (response rate, 24/26).
compared to the predicted final height.1,5 Selecting patients for high- Results Final height was significantly (P < 0·001) reduced, by
dose oestrogen therapy depends on an accurate estimation of final 2·4 ± 3·2 cm, as compared to predictions. High-dose 17β-estradiol height: treatment is usually considered only when the predicted final therapy decreased growth velocity and significantly increased skele- height exceeds 3 SDs above the mean in the general population.6,7 tal maturation (P < 0·001). Linear growth after treatment discon- Thus, predicting final height plays a crucial role in the manage- tinuation was 3·3 ± 1·9 cm. No serious side effects were recorded.
ment of children with CTS.6,8 The most widely used method for pre- Most of the patients were satisfied with the treatment.
dicting final height, which was devised by Bailey and Pinneau (BP Conclusion High-dose 17β-estradiol was moderately effective in
method), is well suited to clinical practice but is highly dependent reducing final height and should probably be reserved for selected on the ability to obtain an accurate estimation of bone age.9–11 Height patients, particularly as knowledge on potential long-term side prediction using the BP method in children with CST has been found inaccurate in boys but clinically acceptable in girls.6 (Received 9 June 2005; returned for revision 21 July 2005; finally Numerous publications have confirmed the effectiveness of high- revised 19 September 2005; accepted 1 December 2005) dose oestrogen therapy in slowing linear growth in girls.
Other studies found that high-dose oestrogens accelerated bonematuration.7,12–14,16–19 To date, the main oestrogens used for growthinhibition have been conjugated oestrogens and ethinyl oestra-diol.12,20,21 Side effects of high-dose oestrogen therapy for growthinhibition have been reported, and the risk/benefit ratio remainsunclear, most notably regarding the risk of cancer22 and thromboem- Correspondence: E. Thibaud, Department of Paediatric Endocrinology and bolism.23–25 As compared to conjugated oestrogens or ethinyl oestra- Gynaecology, Necker-Enfants Malades Hospital, 149,rue de Sèvres, 75743 Paris cedex 15. France. Tel.: +331 44494801; Fax: +331 44494800; β oestradiol has shown a better metabolic safety profile, with E-mail: less weight gain, dyslipidaemia and thromboembolism.26 In this study, we therefore examined the height-limiting effect and tolerance of oral 17β estradiol in 26 constitutionally tall girls.
Results are reported as mean (SD) values with the 95% confidenceinterval (95%CI) and standard error (SE). Student’s t-tests were per- Subjects and methods
formed, and analysis of variance was used to evaluate the influence Between 1989 and 2000, 26 premenarchal constitutionally tall girls of variables on treatment effects. P value of < 0·05 were considered completed 17β-estradiol treatment at the Paediatric Endocrinology and Gynaecology Department of the Necker-Enfants Malades Teach-ing Hospital, Paris, France. CTS was defined as a height (expressed as the SD of observed height for age) equal to or greater than 2 SDsat referral, after exclusion of other causes of excessive growth. Treat- ment was offered to patients who requested height-limiting therapyand whose predicted height was at least 179 cm (+3 SD for the gen- At baseline, mean chronological age was 12·06 ± 1·51 years and mean eral population in France).27 Consent of the parents was obtained.
height was 171·1 ± 6·5 cm with a height SDS of 4·5 ± 0·24. Mean The girls were treated with 4·0–8·0 mg/day of 17β-estradiol, com- treatment duration was 1·62 ± 0·76 years. Predicted final height bined with the progestogen chlormadinone acetate, 10 mg/day and ± 4·3 cm, height at treatment discontinuation was 15 days/month to induce cyclic bleeding and to avoid over-stimulation 179·7 ± 3·7 cm and final height was 183·0 ± 4·2 cm. The mean reduc- of the endometrium. The dose of 8 mg of 17β-estradiol was chosen tion in final height was 2·4 ± 3·2 cm, which was statistically signifi- in the majority of patients because of the following bioequivalence: 8 mg is equivalent to 0,10 mg of ethinyl oestradiol and because it has Throughout treatment, skeletal maturation was accelerated and been found to be efficacious for height reduction in tall stature.28 The growth rate was decreased. During the first 6 months of therapy, treatment was stopped when bone age reached 14 years. This BA was bone age increased by 1·0 ± 0·33 years, indicating a significant accel- chosen at the beginning of the study because it meant that that at eration of bone age (P < 0·001) consistent with 17β-estradiol- least 98% of growth had been completed. Throughout treatment, induced stimulation of cartilage maturation. Bone age acceleration patients were evaluated at 6-month intervals for measurement of remained significant when the first year of treatment was considered body weight and height, Tanner stage determination and recording (Table 3). After treatment discontinuation, height continued to of side effects. All height measurements were performed using the increase, with the mean gain being 3·3 ± 1·9 cm. Thus, final same stadiometer. Radiographs of the left hand and wrist were also height was significantly higher (P < 0·001) than height at treatment obtained at each evaluation for bone age assessment, which was per- discontinuation. However, the final height predicted at treatment formed by a single experienced physician using the Greulich and Pylemethod.10 Bone age acceleration was calculated based on the boneage increase from baseline to the 6- and 12-month time points. Final Table 2. Height parameters during and after high-dose 17β-oestradiol
therapy in 26 girls with constitutionally tall stature
height was predicted using the tables of Bayley and Pinneau.9 Finalheight reduction was computed as the difference between predicted height at baseline and observed final height (see succeeding discus- sions). Plasma levels of cholesterol, triglycerides (n = 10) and glucosewere measured to monitor safety.
All patients were sent a questionnaire by mail at least 2 years after treatment discontinuation. The questionnaire items included height, which was therefore used as final height in the study, treatment Predicted height at end of treatment 183·1 3·3 0·68 181·6–184·5 acceptance, patient satisfaction with the treatment, body weight and regularity of menstrual cycles. Of the 26 patients, 24 returned com- Table 1. Baseline clinical features in 26 girls with constitutionally tall stature
treated with high-dose 17β-oestradiol
Table 3. Bone age and growth rate during high-dose 17β-oestradiol therapy
in 26 constitutionally tall girls
*Bone age acceleration was calculated as the difference between baseline bone age and age after 6 and 12 months of therapy, divided by 6 and 12 months, 2006 Blackwell Publishing Ltd, Clinical Endocrinology, 64, 423–428
High-dose 17β-estradiol in tall girls 425
Table 4. Height parameters during and after high-dose 17β-oestradiol therapy in the three patient subsets based on the relationship between bone age and
chronological age (overall population, n = 26)
discontinuation was not significantly different from the final heightrecorded at last follow-up.
To evaluate the effect of therapy according to bone maturation at baseline, we divided the patients into three groups based on whetherbone age at baseline was less than chronological age (BA < CA,n = 10), equal to chronological age (BA = CA, n = 7) or greater thanchronological age (BA > CA, n = 9) (Table 4). The BA < CA grouphad the highest values for mean baseline height (174·5 cm) and finalheight (183·8 cm); post-treatment growth was 3·4 cm and finalheight reduction was 2·4 cm. The BA = CA group had the lowestvalues for mean baseline height (167·2 cm), final height (179·1 cm),post-treatment growth (2·4 cm) and final height reduction was3·0 cm. In the BA > CA group, mean baseline height was intermediatebetween the other two groups (170·4 cm). This group had thehighest values for predicted final height (187·2 cm), final height(184·3 cm) and post-treatment growth (3·6 cm); final height reduc-tion was 2·9 cm. By analysis of variance, none of these differenceswas statistically significant. Thus, the relationship between bone ageand chronological age at baseline had no influence on treatment Fig. 1 Body mass index (BMI) variations during the first 2 years of 17β-
effects in our cohort of 26 patients.
oestradiol therapy in 26 girls with constitutionally tall stature (values in the upper panel and with percentile according to age in the lower panel).
Overall tolerance was good in our group of patients. No serious side The questionnaires showed that 19 of the 24 respondents were effects were noted. Five girls had one or more of the following: satisfied with the treatment, that three wished they had not received fatigue, nausea, breast discomfort, abdominal pain and triglyceride it, and that two were neither satisfied nor dissatisfied. Greater post- elevation. However, breast discomfort was reported by a single treatment growth was noted in patients who were dissatisfied.
patient, suggesting that high-dose 17β-estradiol therapy may havelittle influence on breast development.
Glucose metabolism was normal in all patients. Of the 10 patients who underwent triglyceride assays, only one had triglyceride eleva- Our data suggest that high-dose 17β-estradiol was effective in reduc- tion during therapy with a return to normal after treatment ing final height when started in premenarchal girls with CST. The discontinuation. No blood pressure changes were found, and no mean reduction in final height was 2·4 ± 3·2 cm, in keeping with thromboembolic events were recorded. Body mass index during earlier studies reporting corrected and uncorrected reductions in the treatment did not vary significantly (Fig. 1). Spontaneous cyclical 2·1–10·0 cm range.6,12,19,29 The mean age and bone age were rather bleeding occurred in 24 patients within 6 months and in two patients advanced at start of treatment, a factor that may have contributed within 11 months after treatment discontinuation. These data to the modest result. Furthermore, the result was less marked than suggest that side effects were mild during treatment, although the expected because treatment was stopped at a bone age of 14 years small sample size and short follow-up should be borne in mind. No which, a posteriori, was too early. Finally we used self-reported side effects were reported after treatment discontinuation.
height, which has been shown to be well correlated with measured 2006 Blackwell Publishing Ltd, Clinical Endocrinology, 64, 423–428
height.30,31 There is even a tendency in these studies to increase self- Furthermore, we did not evaluate potential long-term side effects.
reported heights. In our study this would have reduced the apparent The current uncertainty regarding the risk/benefit ratio of high- beneficial effect of the height reduction therapy. However, com- dose oestrogen height-limiting therapy should be borne in mind. In parisons are hampered by differences across studies regarding base- particular, whether oestrogen height-limiting therapy increases the line clinical features (most notably chronological age and bone age), risk of cancer of the breast or other sites remains unclear. In our treatment duration, therapeutic regimen (dose and nature of the study, a single patient reported breast discomfort, and no clinically oestrogen preparations) and the time of final height assessment.28,32,33 significant breast disease was observed. This finding is in agreement Skeletal maturation was significantly accelerated throughout the with earlier studies.1 However, long-term data on the breast cancer first treatment year in our study, and growth velocity decreased risk after high-dose 17β-oestradiol height-limiting treatment are not concomitantly. These data are consistent with in vitro evidence that high-dose oestrogens stimulate cartilage maturation without We consider that the benefits from high-dose 17β-estradiol increasing growth velocity and that oestrogens accentuate the age- therapy in terms of height reduction were moderate. Furthermore, related decrease in chondrocyte size.34,35 although high-dose 17β-estradiol seems safe in the short term, Mean post-treatment growth was 3·3 ± 1·9 cm in our study, in harmful long-term effects cannot be excluded. Nevertheless, 17β- agreement with previous data.6,11,19,23 The cause of post-treatment estradiol therapy may deserve consideration in girls with a very tall growth is unclear. Mean bone age at treatment discontinuation in predicted final height, no family history of breast cancer and no our study was 14 years. Conceivably, treatment was stopped before family or personal history of dyslipidaemia or coagulopathy.
complete epiphyseal closure, allowing for subsequent growth. Alter- New approaches to the pharmacological treatment of CTS in girls natively, late pubertal completion of spinal growth may lead to an are needed. Drugs that influence GH secretion, such as the somato- additional gain in stature after treatment discontinuation.6 statin analogues octapeptide and lanreotide, have been widely used The marked interindividual variability in final height reduction to treat acromegaly for the last decade and have also been evaluated suggests that a subgroup of patients may derive greater benefit from in CTS.43,44 The GH receptor antagonist pegvisomant is being devel- treatment than the overall population. Our analysis of subgroups oped as an agent that antagonizes GH effects without acting on the defined by the relation between bone age and chronological age at pituitary gland or inhibiting GH secretion. This agent may prove an baseline, however, found no statistically significant differences were attractive alternative to oestrogens for final height reduction.45 How- found regarding final height, growth reduction or post-treatment ever, further studies are needed to assess this possibility.
growth. Thus, one or more unknown factors may underlie the inter- In summary, our study shows that high-dose 17β-estradiol individual variability in treatment efficacy; variations in oestrogen treatment is moderately effective in reducing the final height of girls receptor behaviour may be among these factors.
with CTS. This treatment induces significant skeletal maturation and No serious side effects were noted. Of 26 patients, 5 experienced a decrease in growth velocity. The post-treatment growth in our fatigue, nausea, increased pigmentation, breast discomfort and/or patients may be ascribable in part to the fact that bone age was only abdominal pain. All side effects resolved after treatment discontinu- 14 years at 17β-estradiol discontinuation. No serious side effects ation, and no thromboembolic events occurred. These findings were noticed. Most of the patients were satisfied with the treatment.
support published data. High-dose ethinyl oestradiol or conjugated Nevertheless, the moderate treatment effect and the continuing oestrogen therapy have been reported to cause adverse effects, most uncertainty about the long-term safety of high-dose 17β-estradiol of which were mild and reversible. The adverse event rate may be therapy indicate a need for caution. Research is needed to develop dose-dependent.20,33 Serious adverse events such as thromboembo- lism seem exceedingly rare.36 Triglyceride elevation occurred in one ofour patients but resolved after treatment discontinuation. Similarly, Acknowledgements
in earlier studies,37,38 lipid changes proved reversible after treatmentdiscontinuation. There was no evidence up to 2004 that high-dose U.R. was supported by a grant from ‘Groupement Français de Gyné- oestrogen therapy causes long-term alterations in reproductive cologie de l’Enfance et de l’Adolescence’.
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