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Endocrine Care |
Division of Pediatric Endocrinology, Department of Pediatrics, Christian-Albrechts University, Kiel 24105, Germany
Address all correspondence and requests for reprints to: Prof. Dr. Wolfgang G. Sippell, Department of Pediatrics, Schwanenweg 20, D-24105 Kiel, Germany. E-mail: . sippell{at}pediatrics.uni-kiel.de
Abstract
Estrogens have been shown to rapidly inhibit longitudinal growth in tall boys. To antagonize the initial growth accelerating effect of T, 41 boys with an initial height prediction in excess of 203 cm were treated prospectively with either T enanthate (TE) 250 mg/wk im in combination with ethinylestradiol (EE2) 0.1 mg/d taken orally for the first 5.8 ± 0.47 wk (mean ± SE) of treatment (group 1, n = 20) or with TE alone (group 2, n = 21). Patients were randomized to one or the other treatment regimen. Mean (±SE) predicted adult height was 206.8 ± 0.7 cm in group 1 and 206.4 ± 0.8 cm in group 2. Total duration of treatment was 16.1 ± 0.8 months and 14.0 ± 1.2 months in group 1 and 2, respectively (NS). EE2-induced side effects in group 1 (gynecomastia) were limited and fully reversible. No negative long-term sequelae were found at final height with respect to hypothalamic-pituitary-gonadal axis activity and to testis volumes. Although there was a tendency to a lower initial growth velocity measured by knemometry in group 1 (0.30 ± 0.05 vs. 0.38 ± 0.05 mm/wk, NS), final height did not differ in both study groups (195.0 ± 0.8 cm in group 1, 194.6 ± 0.8 cm in group 2). Similarly, height reduction (initial predicted adult height minus final height) was not significantly different between the two groups (12.0 ± 0.9 cm in group 1, 11.7 ± 0.9 cm in group 2). In conclusion, the addition of EE2 during the initial treatment phase to high-dose T in tall boys has no significant effect on height reduction. The results of this clinical trial suggest that the initial growth inhibiting effect of EE2 on the epiphyseal growth plates is overridden by the long-term administration of high dose TE.
IN THE MANY reports on high dose T treatment of constitutional tall stature (CTS) in boys (1, 2, 3, 4, 5, 6), no report has dealt with a combination therapy of T and E2.
T has been proven to reduce final height compared with pretreatment predicted adult height (PAH) (1, 6, 7, 8). At the beginning of T treatment, a marked acceleration of height velocity is observed. This is caused by the synergistic effect of elevated GH and IGF-I levels (9, 10, 11) and the anabolic effect of T per se (12, 13).
In contrast, estrogens decrease height velocity instantly and were shown to act in a dose-dependent manner even in low doses (14, 15). The mode of action of estrogens in humans is thought to be the decrease of IGF-I (14, 16). This effect has also been demonstrated in adult men (16). Furthermore, the decelerating effect of short-term estrogen administration on height velocity has been shown in tall boys (17).
The importance of estrogens for bone maturation and epiphyseal closure in males has generally been acknowledged (18). For instance, incomplete epiphyseal closure and continued linear growth into adulthood has been reported in a man with estrogen resistance (19) and in a phenotypic female with aromatase deficiency (20).
To antagonize the initial growth accelerating effect of T alone, we combined ethinylestradiol (EE2) with T in the early stage of treatment of CTS in boys in a prospective randomized study with the aim to investigate the long-term effect of such a combination regimen on final height reduction.
Patients and Methods
Patients
Forty-one pubertal boys with tall stature aged 13.7 ± 0.2 yr (mean ± SE; range 11.7–16.8 yr) were randomly assigned to one of two treatment regimens. Patients of group 1 were treated with T enanthate (TE; Testoviron-Depot-250, Schering AG, Berlin, Germany) in a dose of 250 mg/wk im in combination with EE2 (Progynon C, Schering AG, Berlin, Germany) in a dose of 0.1 mg per day orally, which was administered for the first 4–12 wk of treatment only. Patients of group 2 received TE alone in the same dose as group 1. The study was approved by the Medical Faculty’s Ethical committee.
Patients were studied prospectively before treatment, after 6 months of treatment, at the end of treatment, and at final height (11.9 ± 3.7 months after end of treatment). Mean treatment duration was 15.1 ± 0.7 months (range 7.8–35.3 months). Treatment was terminated when bone age (BA) was above 16 yr, and knemometric height velocity approached zero. The entire observation period comprised 92 patient years. All patients presented with constitutional tall stature. Patients with tall stature resulting from a syndrome were excluded from analysis.
Materials and Methods
Pubertal stages were determined according to Marshall and Tanner (21). Testicular volume (TV) was estimated by orchidometry. Height was measured with a Harpenden stadiometer and knemometric measurements were carried out as described previously (22). Stadiometric height velocities were calculated over observation periods of at least 6 months. Knemometric growth rates were expressed as mm/wk. German normative data (23) were used for calculation of height SD score (SDS). Bone age was estimated by the Greulich and Pyle method (24), and PAH was calculated according to Bayley and Pinneau (25). Final height was assumed when total body height velocity had fallen below 1.0 cm/yr.
Plasma gonadotropins were determined by enzyme immunoassay (Serozyme, Serono Diagnostika, Freiburg, Germany). The sensitivity of the assay was 0.3 IU/liter for LH and FSH (26). A value of 0.2 IU/liter was assigned to LH and FSH levels below the detection limit. Reproducibility within and between assays was 4.0% and 8.9% for LH and 2.9% and 8.0% for FSH, respectively. T was determined by specific RIA after extraction and LH-20 chromatography (27, 28). Sensitivity was 3 ng/dl, intraassay and interassay coefficients of variation were 4.5% and 12.2%, respectively. Dehydroepiandrosterone sulfate (DHAS) was determined using a commercial RIA kit (Diagnostic Products Corp., Los Angeles, CA). Intraassay and interassay coefficients of variation were 4.6% and 14.0%, respectively.
Statistical analysis
Data were evaluated for normal distribution and are presented as mean and SEM (SE). For statistical comparison between the study groups the two-sided t test for unpaired samples was used. Comparisons within groups between multiple time points were made by Friedman’s ranked ANOVA. The Newman-Keuls test was used as post hoc test. Rates of patients achieving predefined treatment goals (height reduction 
5 cm or 10 cm) were compared between groups by Fisher’s exact test. P < 0.05 was considered significant.
Results
Clinical data
We investigated 41 pubertal boys with CTS in two groups in a prospective trial. Group 1 (n = 20) was treated with TE in combination with EE2 and group 2 (n = 21) with TE alone.
At start of treatment, BA and chronological age (CA) were 13.3 ± 0.2 yr and 13.7 ± 0.2 yr in group 1 and 13.4 ± 0.2 yr and 13.7 ± 0.3 yr in group 2, respectively. Pubertal stages ranged from P2 to P5, from G2 to G5, and from TV 5.5 ml to 20 ml in group 1 and from P1 to P5, from G1 to G5, and from TV 2 ml to 20 ml in group 2. Pubertal stages were well comparable between group 1 and group 2. There was no statistically significant difference in any clinical, auxological, and hormonal variable between groups 1 and 2 (Table 1
). At final evaluation, CA was 15.8 ± 0.2 yr in group 1 and 15.7 ± 0.2 yr in group 2. There was no significant difference in TV between the two study groups (15.3 ± 1.0 ml in group 1 vs. 15.0 ± 1.2 ml in group 2; Table 2).
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). There was a physiological increase in BMI to 21.8 ± 0.4 kg/m2 in group 1 and to 21.7 ± 0.3 kg/m2 in group 2 during treatment (P < 0.05 vs. pretreatment). BMIs remained unchanged at final evaluation (Table 2; NS between groups 1 and 2). Hormonal data
Basal plasma LH was 2.0 ± 0.3 IU/liter and 2.2 ± 0.3 IU/liter, and basal FSH was 4.4 ± 1.1 IU/liter and 4.5 ± 0.7 IU/liter in group 1 and 2, respectively. After a standard GnRH test (60 µg/m2 iv) an LH peak of 20.2 ± 1.9 IU/liter and of 17.0 ± 1.5 IU/liter and an FSH peak of 7.5 ± 1.9 IU/liter and of 7.0 ± 1.1 IU/liter were seen in groups 1 and 2, respectively. Basal and stimulated gonadotropins were within normal limits for age, sex, and stage of puberty. There was no significant difference in plasma T and DHAS levels between the two study groups (Table 1).
At final evaluation, 11.9 ± 3.7 months after end of treatment, we repeated the GnRH test to prove restitution of pituitary-testicular function. Basal plasma LH (2.9 ± 0.5 IU/liter) and basal FSH (5.9 ± 1.1 IU/liter) in group 1 were both higher than initial values (ns for LH and P < 0.02 for FSH), according to pubertal development (21). In group 2, we found comparable values of basal LH (3.0 ± 0.4 IU/liter: P < 0.04 vs. pretreatment) and basal FSH (7.0 ± 1.1 IU/liter: P < 0.001 vs. pretreatment).
GnRH-stimulated LH was 24.1 ± 3.1 IU/liter and FSH was 13.8 ± 3.7 IU/liter in group 1 (NS for LH and P < 0.02 for FSH vs. pretreatment, respectively) and 18.8 ± 1.6 IU/liter and 11.3 ± 1.7 IU/liter in group 2 (NS for LH and P < 0.001 for FSH vs. pretreatment, respectively). There were no significant differences for peak LH and FSH between group 1 and group 2, respectively. T plasma levels were 15.9 ± 1.6 nmol/liter and 15.7 ± 1.4 nmol/liter in groups 1 or 2, respectively (NS). A significant increase of T from pretreatment levels was seen in group 2 (P < 0.02), but not in group 1. There was a significant increase of plasma DHAS levels from pretreatment to final evaluation in both study groups; however, no significant differences were found between groups 1 and 2 (Table 2).
Growth and bone maturation
At start of treatment, patients of both groups showed comparable heights (185.7 ± 1.3 cm vs. 183.7 ± 1.6 cm in groups 1 and 2, respectively). After 6 months of treatment, height was 190.3 ± 1.0 cm in group 1 and 190.2 ± 1.2 in group 2 (NS; Fig. 1). Final height was 195.0 ± 0.8 cm in group 1 and 194.6 ± 0.8 cm in group 2 (NS). Height gain during sex steroid treatment showed no significant difference between the two study groups (8.7 ± 1.2 cm in group 1 and 11.0 ± 1.3 cm in group 2). The height reduction calculated as final height minus initial PAH was slightly but not significantly higher in group 1 (12.0 ± 0.9 cm) than in group 2 (11.7 ± 0.9 cm; Fig. 1). A separate analysis of patients 
13.5 yr (group 1: n = 11; group 2: n = 11) and patients > 13.5 yr (group 1: n = 9; group 2: n = 10) at start of treatment showed no difference in height reduction in group 1. However, younger patients of group 2 had a significantly greater height reduction than the older patients (13.7 ± 0.9 cm vs. 9.6 ± 1.3 cm; P < 0.05).
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). Height gain after end of treatment was 1.39 ± 0.50 cm in group 1 and 2.07 ± 0.52 cm in group 2 (NS).
The development of PAH is shown in Fig. 1. PAH significantly decreased during treatment. There was no significant difference between the two study groups. At the end of therapy, BA was 16.7 ± 0.1 yr in group 1 and 16.6 ± 0.2 yr in group 2 (NS). The rate of bone maturation (
BA/CA) over the entire treatment period showed no difference between group 1 and group 2 (Table 3). While height increased markedly during treatment to a final height of 195.0 ± 0.8 cm in group 1 and to 194.6 ± 0.8 cm in group 2, height SDS for CA remained almost constant in both groups (2.7 ± 0.1 in group 1 and 2.7 ± 0.1 in group 2). With respect to final height, there was no difference between both groups (Table 2). There was no significant correlation of the duration of additional EE2 treatment with height reduction.
All patients in both study groups achieved a height reduction of 5 cm. A height reduction of 10 cm was seen in 77.8% of patients of group 1 and in 66.7% of group 2 patients (NS).
Side effects
In group 1 (TE + EE2 group) we noted growth of breast parenchyma during treatment with EE2 up to pubertal stage B3 (29). In 14 of 20 boys, there was notable breast development. In 11 of 14 cases a breast stage B2 and in 3 of 14 breast stage B3 was observed. In some patients, estrogen treatment had to be terminated after a few weeks because of breast development. At the end of treatment breast development disappeared in all cases. At final investigation there was no breast development present.
Side effects related to T were detected in almost all cases in both groups, e.g. slight to moderate acne vulgaris or male pattern of body hair. We saw severe acne vulgaris in only one case in the TE + EE2 group. In the TE group severe acne conglobata in two cases led to termination of treatment. In this group we also found one patient with a knee joint effusion that disappeared spontaneously after 4 wk under continuation of treatment. Gynecomastia was not seen in group 2.
No negative long-term effects on TV was seen. TV were comparable between the study groups before treatment and at final evaluation.
In one patient in group 1, general weakness which led to slight school problems was reported.
Discussion
This study was designed to evaluate whether or not treatment with T plus EE2 initially is more effective in reducing final height in boys with CTS than T alone. In contrast to other studies using either treatment with T alone (1, 2, 3, 4, 5, 6) or short-term treatment with estrogen alone (17) in boys with CTS, we combined both treatment regimens to antagonize the T-mediated acceleration of height velocity during the initial treatment phase (1, 7, 8). To our knowledge, a similar therapeutic approach has not yet been reported. Both patient groups were homogeneous according to clinical, auxological, and hormonal data before treatment. The homogeneity of study groups is important because the responsiveness of cartilage and bone cells to sex steroids is sex specific and age dependent (30). We used a T dose of 250 mg/wk im (approximately equivalent to 500 mg/m2). This dose has been used in most studies (1, 3, 4, 5) and corresponds to roughly 4 times the normal daily T production rate of adult men or 8–10 times that of early adolescence.
Short-term, low-dose treatment with EE2 was shown to accelerate total ulnar growth in boys, whereas supraphysiologic doses of EE2 led to an unchanged total ulnar growth, known as a biphasic dose response of growth velocity (31). According to these results and to in vitro findings of stimulatory E2 effects on cartilage maturation without increasing the growth plate (32), we choose the low- dose EE2 treatment regimen. Definitions of low dose EE2 (100 ng/kg·d) and high-dose EE2 (400–800 ng/kg·d) were established in the context of treatment of Turner’s syndrome (33).
van den Bosch et al. (17) administered 0.05 mg of EE2 daily for 6 wk to 10 CTS boys and showed a significantly reduced ulnar growth velocity during EE2 treatment. After cessation of EE2, ulnar growth rate almost doubled.
In contrast to these results, we did not see a significant reduction in initial knemometric growth rate with the addition of EE2 to the T treatment in comparison to T alone.
Similarly, there was no significant difference between both groups in stadiometric height velocity during the first 6 months of treatment. In both groups, a highly significant further decrease of both knemometric growth rate and stadiometric height velocity was seen at the end of treatment, compared with the period during and at start of treatment. This reflects the expected efficacy of treatment with T as such and excludes negative effects of EE2 on the intended reduction of height velocity in CTS boys (1, 2, 3, 4, 5, 17).
The duration of EE2 administration is of great importance. A recent study suggests that acute and chronic EE2 exposure may have different effects on GH secretion: acute infusions decrease, whereas prolonged exposure may increase GH bioactivity (34). The rate of aromatization of T into E2 in our patients is unknown. Possibly, after cessation of EE2 administration, a low conversion rate led to local E2 levels similar to that with low-dose EE2 treatment, with a stimulatory effect on longitudinal growth (31). Similarly, patients with familial male precocious puberty who were treated with antiandrogens alone did not revert to a normal prepubertal growth rate until an aromatase inhibitor was added (35). It could be speculated that the growth rate in boys with CTS might be suppressed more effectively by a combination therapy of T and EE2 as in our study, and by the addition of an aromatase inhibitor after the withdrawal of E2. It is interesting to note that the remaining growth after end of treatment was similar in both groups.
Final height was comparable between both groups (195.0 ± 0.8 cm vs. 194.6 ± 0.8 cm). Height reduction was 12.0 ± 0.9 cm in group 1 and 11.7 ± 0.9 cm in group 2 with no significant difference between the two study groups. In other studies, mean height reduction ranged from 4.8 ± 0.6 cm (4) to 11.4 ± 2.1 cm (36), according to the same method of height prediction as was used here (25). The rather favorable results in our present study are probably due to an early start of treatment in terms of BA (mean of 13.4 yr), of statural height (mean of 184.6 cm) and of a high initial PAH (mean of 206.6 cm) as an indication for therapy. It has been clearly shown that height reduction was more pronounced when treatment was started at a younger BA (3, 4, 5, 36, 37). Starting at a younger CA yielded higher height reductions than a later start of treatment (>13.5 yr) in our group 2. Furthermore, a significant negative correlation between posttreatment growth and BA at the time of stopping therapy was observed (4). We adjusted the end of treatment individually according to BA (mean 16.6 ± 0.09 yr) and to short-term growth velocity measured by knemometry (mean 0.10 ± 0.02 mm/wk). Overall height reduction was significant after 6 months of short-term treatment with high-dose T in a group of boys with a mean BA of 15.3 ± 0.8 yr at end of treatment (37). However, this finding could not be reproduced (38), suggesting that the bone age at end of treatment is an important factor determining height reduction. Thus, it can be concluded that longitudinal bone growth was almost completed after an average treatment duration of 15.1 months in our patients. Therefore, residual height increment after end of treatment was negligible. In the literature, no data are available about the height increment after end of therapy.
In both study groups, each individual patient did show a final height reduction compared with his initial PAH. This treatment goal has not always been reached in other studies in which a marked variation in the individual height-reducing effect was seen, ranging from -2.6 cm to +15.8 cm (1, 3, 4, 5, 6). In our study, height reduction ranged from +5.6 cm to +22.2 cm in group 1 and from +5.5 cm to +19.9 cm in group 2. The Bayley-Pinneau adult height prediction method used in our present study is known to systematically overpredict in tall boys in a range of approximately + 2 cm (39). However, even taking into account the overestimation of height prediction, our study still shows favorable height reduction in all patients.
Basal and stimulated gonadotropins showed some, however, not always significant increases between initial and final evaluation. At both time points, gonadotropins before and after GnRH stimulation showed no statistically significant difference between group 1 and group 2 (Table 1 and 2). Because T levels were in the adult range already before treatment in several patients, no significant increase to the final evaluation was noted in group 1, although this was the case in group 2. In both groups, pituitary-gonadal function was restored after treatment.
EE2 has been shown to cause gynaecomastia in boys after 6 wk of treatment in a dose of 0.05 mg daily (17). The same was seen in our patients with an EE2 dose of 0.1 mg/d. Breast development was reversible in all but one boy after stopping EE2 treatment during continuation with high-dose T. Breast development was absent in all boys at final evaluation. There was no negative long-term effect on testicular size or function.
In the boys with T treatment, side effects were as could be expected from the reports in the literature (1, 2, 3, 4, 5, 37, 38, 39). Mild to moderate acne was the most important side effect seen in most boys. Severe acne was reported anecdotically in boys treated for tall stature (40). The rate of premature treatment termination due to severe acne (4.9% of patients) was comparable to other reports (1, several cases out of 29 patients treated; 5, 3.1%).
In conclusion, this report demonstrates that high dose T treatment for tall stature in boys yields good results in terms of height reduction (range, 5.5–22.2 cm) if treatment is initiated early enough and treatment is carried out until a bone age of about 17 yr is reached. The additional treatment with EE2 in a dose of 0.1 mg/d does not lead to an earlier fall in height velocity and is of no advantage with respect to height reduction.
Acknowledgments
We acknowledge the helpful advice of Dr. M. Hermanussen (Aschauhof, Germany) in planning and initiating this study. We are grateful to Karin Benoit for the meticulous performance of the knemometric and stadiometric measurements. We thank Stefanie Kasch, Susanne Olin, Sabine Stein, and Silke Struve for their expert technical assistance with the hormonal analyses. We also thank Joanna Voerste for linguistic editing of the manuscript.
Footnotes
Abbreviations: BA, Bone age; BMI, body mass index; CA, chronological age; CTS, constitutional tall stature; DHAS, dehydroepiandrosterone sulfate; EE2, ethinylestradiol; PAH, predicted adult height; SDS, SD score; TE, T ethanate; TV, testicular volume.
Received May 7, 2001.
Accepted December 12, 2001.
References
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