Endocrine Reviews 19 (5): 540-558
Copyright © 1998 by The Endocrine Society
Sex Steroid Treatment of Constitutionally Tall Stature1
Stenvert L. S. Drop,
Wouter J. de Waal and
Sabine M. P. F. de Muinck Keizer-Schrama
Department of Pediatrics, Division of Endocrinology, Sophia
Childrens Hospital, Erasmus University, 3000 CB Rotterdam, The
Netherlands
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Abstract
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- I. Introduction
- II. Normal vs. Extremes of Growth
- A. Defining CTS
- B. Endocrinology of CTS
- III. Endocrinology of Bone Growth and Maturation
- IV. Sex Steroid Action on Bone Growth and Maturation
- V. Height Prediction
- A. Skeletal maturity or BA
- B. Computed assisted skeletal age-scoring systems
- C. Accuracy of height prediction
- D. New prediction equations in constitutionally tall children
- VI. Treatment of CTS: General Concepts
- VII. Treatment of Constitutionally Tall Boys
- A. T treatment modalities
- B. Height reduction
- C. Effects on gonadal function
- D. Other clinical effects
- VIII. Estrogen Treatment in Tall Girls
- A. Estrogen treatment modalities
- B. Height reduction
- C. Effects on gonadal function
- D. Other adverse effects
- IX. Alternative Treatment Modalities and Future Research
- X. Conclusions and Recommendations
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I. Introduction
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WHILE as many children grow above the 97th percentile
(corresponding to + 1.8 SDs) as below the 3rd percentile,
tall stature is a far less common reason for seeking medical attention
than short stature. Tall stature is more easily accepted in society and
may even be an advantage. This holds specifically true for boys, and
girls are more often referred.
Growth is a result of complex processes. Genetic constitution,
nutrition, endocrine function, and psychosocial well being are all
involved in the process of growth (1, 2). The genetic component of
height has been estimated to be 0.50.9, i.e., 5090% of
the height variation is accounted for by genetic factors. Assessment of
the parental height as an indicator of the genetic component of growth
and development of the child is therefore of critical importance (3).
In addition, socioeconomic factors such as social class, family size,
birth rank, housing, and crowding are associated with growth. Improved
socioeconomic conditions and better health have led to the
manifestation of a positive secular trend in growth and development
over the last centuries. In 1865 the mean adult height among Dutch army
recruits was 165 cm. One century later, in 1965, the mean adult height
in boys was 178 cm. Fifteen years later, in 1980, the mean adult height
had increased by another 4 cm to 182 cm. In the middle of the 19th
century, age of menarche of European girls was about 1617 yr.
Nowadays, the mean age of menarche is 13 yr or even less.
Phenomena responsible for both positive and negative secular trends
have affected height throughout our history. Studies of fossil remains
of our hominid ancestors demonstrate that the stature of individuals
living during the last hundred-thousands of years reached the range of
heights seen today: the mean stature of early anatomically modern
Homo sapiens in Europe was 184 cm in males and 167 cm in
females (4, 5). Thus, stature is based on many factors, including
heredity and environment.
In recent years, information concerning auxology and
(neuro)endocrinology of tall stature has expanded. In addition,
long-term results of height-reducing treatment modalities have become
available. In this review we will give an update of the
(neuro)endocrinology, the auxology, the differential diagnosis, and the
therapeutic modalities available in the management of constitutionally
tall stature (CTS).
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II. Normal vs. Extremes of Growth
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A. Defining CTS
A thorough understanding of the factors influencing the process of
normal growth is essential to understanding the pathophysiology of the
extremes of growth (6). It has been well established that populations
of various ethnic origin differ considerably in growth and development.
Therefore, reference growth curves have been obtained by measuring
healthy individuals longitudinally or cross-sectionally (or both).
Extremes of growth can be defined knowing the normal variance of growth
of the reference population. Usually an individual whose height differs
more than 2 SDs from the population mean, i.e.,
a child with a height above the 97th percentile of the growth curve, is
considered too tall just as a child growing below the 3rd percentile is
considered too short. It should be emphasized, however, that most of
the children who grow beyond these percentiles are part of a continuum
of a normal distribution curve, and only a minority will have a defined
abnormality.
CTS is defined as a condition in which the height of an individual is 2
SDs above the corresponding mean height for a given age,
sex, and population group. As shown in Table 1
, height p97 values vary
substantially among various populations. The Scandinavians and the
Dutch are among the tallest people in the world.
In CTS, usually one or both parents are tall; thus, genetic and
familial factors are most important etiologically. Mean birth length is
in the 75th percentile, and tall stature becomes evident at the age of
34 yr. Growth velocity is accelerated in early childhood but slows
down after 45 yr of age when the growth curve starts to parallel the
normal curves (19).
The diagnosis is generally made from the family history of growth and
from physical examination. No apparent abnormalities are present at
physical examination, which permits distinction from excessive growth
syndromes such as Marfan syndrome and Klinefelter syndrome (see Table 2
).
B. Endocrinology of CTS
A significant positive correlation has been established between
growth and GH secretion in studies of children with various heights
(20, 21, 22). In a recent study, insulin-like growth factor (IGF-I) levels
in prepubertal children correlated significantly with height velocity
in the following year (23). In CTS children, relatively high levels of
IGF-I were measured (24).
At the time of puberty GH secretion increases. Sex-specific changes
regarding the timing of the pubertal increase of GH secretion during
puberty have been found by analyzing 24-h GH profiles in healthy boys
and girls (25). This increase, occurring about 1 yr earlier in girls
than in boys, is correlated to estradiol levels in both boys and girls
(26, 27). Similarly, serum levels of IGF-I rise at puberty (23). In
boys with delayed puberty, testosterone (T) treatment caused increased
GH pulse amplitude, thereby increasing the mean serum GH concentration.
T exerts its effect on GH via an estrogen-dependent mechanism by
increasing hypothalamic GHRH release (28). Paradoxical GH
responses to glucose loading and to administration of TRH or GHRH,
similar to those seen in acromegaly, have been observed in some CTS
children (29, 30, 31). However, these observations have not been
substantiated in studies properly controlled for age and stage of
puberty. Tauber et al. (32) showed a clear heterogeneity of
GH secretion in tall children, with some of them even having low
GH secretion (32). Therefore, abnormal responses may be related more to
the stage of puberty of the child than to abnormalities of GH secretion
(33).
In conclusion, constitutionally tall children are healthy children
without hard evidence of pathology of the GH-IGF-I axis.
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III. Endocrinology of Bone Growth and Maturation
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Given that stature of patients with CTS appears to have a genetic
basis, it is worthwhile to review the biological factors known to
regulate normal skeletal growth. This information is relevant in the
context of the current treatment modalities of CTS, which are based on
sex steroid action on bone growth and maturation (see below).
Longitudinal bone growth is the result of expansion of the growth plate
cartilage. As puberty proceeds, a progressive decrease in cartilage
expansion occurs. Because the vascular invasion and resorption of
calcified cartilage by chondroclasts exceeds cartilage expansion, there
is a progressive thinning of the growth plate. Ultimately, the growth
plate becomes perforated and longitudinal bone growth ceases (34, 35).
The regulation of longitudinal bone growth is very complex, and several
factors, including nutritional, endocrine, paracrine, and autocrine,
are necessary (36). For normal bone growth and maturation the gonadal
steroids are essential in conjunction with several hormones and growth
factors:
1. GH. GH has been shown to stimulate long bone growth in a
dose-dependent fashion. At the cellular level GH interacts with the GH
receptor. The expression of GH receptors is developmentally
regulated in epiphyseal chondrocytes (37). There is ample evidence that
GH interacts directly with cells of the growth plate and not only
through IGF-I (vide infra). Green and associates (38)
have proposed the dual effector theory based on in
vitro observations (see also Ref. 39). This theory states that GH
is a prerequisite of cartilage maturation. Priming of resting
chondrocytes in the growthplate by GH is required for IGF-I to promote
clonal expansion of growth plate chondrocytes and to stimulate
skeletal growth. More recently it has been suggested that this theory
may not apply to the in vivo situation. The presence of GH
receptors is not limited to resting chondrocytes. It was shown that
both IGF-I and GH exerted their effect at each stage of differentiation
rather than acting specifically upon particular subpopulations of cells
at certain phases of chondrocyte differentiation (40). The observation
that GH-overproducing transgenic mice have a significantly larger size
than their controls, while IGF-I transgenic mice have a normal size,
would support the theory of a differential effect of GH and IGF.
However, transgenic models are inadequate for studying the independent
actions of IGF-I and GH as in IGF-overproducing transgenic mice GH
production is not completely suppressed (41).
2. Thyroid hormone. Thyroid hormones are crucial for bone
growth because of their direct effects on bone. In addition, there are
indirect effects by stimulating pituitary GH release (42), thereby
increasing serum IGF-I levels. Lastly, effects of thyroid hormone on
IGF-I generation by chondrocytes have been demonstrated (43). The
obvious experiment of nature is represented by the syndrome of
resistance to thyroid hormone hallmarked by short stature and marked
delayed bone maturation (44).
3. Vitamin D. In addition to the crucial role of vitamin D in
bone mineralization, several observations point to a possible role in
chondrocyte proliferation and bone growth. In rats, proliferation of
growth plate chondrocytes is decreased by high doses and increased by
low doses of 1,25-dihydroxyvitamin D3 [
1,25-(OH)2D3] (45). Moreover, short stature
and delayed bone maturation may be present in the syndrome of vitamin D
resistance (46).
4. Growth factors. As IGF-I and -II are among the most
prevalent growth factors secreted by skeletal cells and have important
actions on bone formation, it is reasonable to predict that they play a
significant role in bone growth and maturation. In the circulation
IGF-I and -II form a complex with IGF-binding proteins, and there is
little, if any, free IGF-I or -II available in bone. Thus, locally
secreted IGF-I and -II acting in a paracrine or autocrine manner might
play an even more important role in the regulation of growth plate cell
function. IGFs enhance the differentiated function of the osteoblast
and increase collagen synthesis. Moreover, IGFs decrease collagen
degradation and IGF-I (but not IGF-II) increases osteoclast recruitment
(41).
The synthesis of IGF-I and -II takes place in cells of osteoblast
lineage and is controlled by systemic hormones (stimulatory: PTH, GH,
estrogens; inhibitory: cortisol, vitamin D) and local factors
(stimulatory: bone morphogenetic proteins, PGE2;
inhibitory: fibroblast growth factor, transforming growth factor,
platelet derived growth factor).
In addition, skeletal cells synthesize a variety of IGF-binding
proteins (IGFBP). They act to regulate and modulate the local actions
of IGFs. Most IGFBPs have been shown to have inhibitory effects on
either IGF-I or -II. However, IGFBP-5 has been shown to potentiate
IGF-II action on osteoblast- derived cell lines (47).
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IV. Sex Steroid Action on Bone Growth and Maturation
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The pubertal growth spurt has long been considered to be an
androgen-dependent process. However, there is abundant clinical and
experimental evidence showing that estrogens may be primarily
responsible for accelerated growth during puberty (48). It is
remarkable that peak height velocity occurs in girls and boys when
estradiol levels are not only low but also quite similar (49, 50).
Still, a direct relationship between levels of E2, GH, and
pubertal growth has not been established (51, 52).
Girls with Turner syndrome show a growth spurt during estrogen
replacement therapy (53, 54, 55). Similarly, girls with central or
pseudo-precocious puberty with clearly elevated estrogen levels show
increased height velocity and premature epiphyseal closure (56).
Whereas in patients with androgen insensitivity syndrome the growth
spurt resembled that of women both in magnitude and timing, mean final
adult height was taller than in normal women but shorter than in normal
men (22, 48, 57). This would suggest that Y chromosome-related factors
contribute to stature. Patients with familial male precocious puberty
treated with antiandrogens alone did not revert to a normal prepubertal
growth rate but only when an aromatase inhibitor was added (58).
Studies of acute infusion of gonadal steroids in peripubertal children
have illustrated the complexity of the relationship between gonadal
steroids and the GH/IGF axis (49, 59, 60). These studies suggest sex
differences in the control of GH secretion in the response to
E2 during puberty. Moreover, acute and chronic
E2 exposure may have different effects: acute infusions
decrease whereas prolonged exposure may increase GH bioactivity (60).
There is also evidence for a dose dependency as high doses of estrogens
result in decreased growth velocity in both males and females (58, 61, 62). High-dose estrogen treatment decreased IGF-I levels in acromegalic
patients as well as in tall girls (63, 64). Recently, a man was
described with estrogen resistance. He had a normal prepubertal growth
and normal timing of onset of secondary sex characteristics. Despite
full masculinization he continued to grow. At 18 yr his height was 204
cm, and the growth velocity was 1 cm/yr. The bone maturation and
mineralization were both markedly retarded (65). Moreover, a phenotypic
female with aromatase deficiency was described showing markedly delayed
bone maturation (66). It is well known that in boys with
pseudo-precocious puberty as a result of congenital adrenal
hyperplasia, height velocity is increased and epiphyseal maturation is
advanced, resulting in stunted adult height. There is ample evidence
that androgen-stimulated growth is largely based on influencing GH
release and augmentation of IGF-I. However, it is not excluded that
these effects are estrogen mediated. On the other hand, nonaromatizable
androgens have growth-promoting effects not mediated via GH-IGF-I axis
(67). Keenan et al. (68) reported that nonaromatizable DHT
induced and maintained accelerated growth rate in short boys with
delayed puberty in spite of a 50% decline in integrated GH
concentration and no change of IGF-I level, suggesting that strictly
androgen-mediated skeletal growth might be exerted locally in growing
cartilage.
In vitro studies using rat- and human-derived cells have
shown that there might be a sex-specific and age-dependent
responsiveness of cartilage and bone cells to sex steroids. Cells and
tissues derived from males respond primarily to T, whereas cells and
tissues derived from females respond primarily to estrogen. The best
response was obtained in tissue from children in early puberty
(69, 70, 71). The mechanism of action of the gonadal steroids on growth
plate cartilage is poorly understood. The effect of estrogens on
proliferation of human chondrocytes in vitro was shown to be
biphasic: at low concentration a stimulatory effect was observed, while
at supraphysiological doses inhibition was observed.
High doses of estrogens stimulate the maturation of cartilage without
increasing the growth rate: cell division by cartilage cells is
inhibited in the proliferative zone of the growth plate, and the
age-related decrease in size of the hypertrophic chondrocytes is
accentuated by estrogens (72, 73, 74, 75, 76). The latter effects were not overcome
by the addition of GH or IGF, suggesting that estrogens may act
directly on chondrocytes or may influence the release of factors that
inhibit cell proliferation locally (77). Using fetal rat osteoblasts in
culture, McCarthy et al. (78) established that estrogens do
not alter IGF-I promotor activity but inhibit the biological effects of
all hormones that act through cAMP to regulate skeletal IGF-I
expression and activity.
Collectively, bone growth and bone maturation are the result of a
complex interplay of various hormones in which GH and the gonadal
steroids have a pivotal role. Moreover, there might be a sex-specific
and age-dependent responsiveness of cartilage and bone cells to sex
steroids. At the level of the growth plate, estrogen receptor-mediated
processes appear essential in expressing the effects of sex steroids.
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V. Height Prediction
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Height prediction plays a key role in the management of children
with growth disorders and consequently in children with CTS.
Therapeutic intervention is based on the estimated height prognosis:
whenever the height prognosis exceeds a certain limit (usually 2
SDs above the mean of the population), treatment might be
considered. Hence, accurate techniques for reliable height predictions
are essential. The suitability and importance of skeletal maturity as a
predictor variable for adult height have long been recognized (79, 80, 81, 82).
The techniques of Tanner-Whitehouse and Bayley-Pinneau both share the
use of bone age (BA) as an indicator of skeletal maturity to estimate
final adult height. The first prediction method uses the BA method
developed by Tanner et al. (80), whereas the latter utilizes
the BA method of Greulich and Pyle (83). Each BA determination is
linked with potential problems as briefly summarized below (84).
A. Skeletal maturity or BA
A measure of skeletal maturity is generally obtained by assessing
the appearance and shape of the bones of the hand and wrist on an
x-ray. These appearances change with age, and their rate of change is a
direct measurement of the rate of maturation. Various methods of
evaluation of BA and maturity have been developed over the years. The
methods most commonly used are the Greulich and Pyle Atlas (83) and the
Tanner-Whitehouse (TW2) method (79, 80). In addition, other methods
such as the FELS-method are also available (85).
The method of Greulich and Pyle for BA estimation is presented
as an atlas of examples of radiographs of the left hand and wrist of
healthy children at various ages (83). The children who form the
standard group were drawn from the Brush Foundation Study, which
selected children from the better socioeconomic strata in Cleveland,
Ohio, from 1930 onward. All the children were white, had been born in
the United States, and were of North European ancestry. Each of the
standards of the atlas was selected from a large number of children of
the same sex and age. All films were arranged in order of increasing
maturity, and the film chosen as the standard is the one most
representative of the central tendency or anatomical mode. The BA is
determined by comparison with the standards.
The Tanner-Whitehouse technique describes maturity indicators for each
bone of the hand and wrist (79, 80). Each bone progresses through a
series of specific stages with assigned weighted scores. These
scores are added to form a maturity score, which in turn can be
converted to a corresponding BA. The source data for this method were
obtained from large groups of British children of an average
socioeconomic level in the 1950s.
The major problem in both techniques is that subjective processes and
discontinuous scales are used that result in considerable inter- and
intrarater variability in BA (84, 86, 87, 88). In a direct comparison, the
BA as determined by the Greulich and Pyle method is generally about 1
year less than that as assessed by the Tanner-Whitehouse technique
(86, 87, 89). One should realize, however, that BA determinations are
estimates of maturity and that, in fact, there is no
objective quantification available. Recently, various authors have
discussed the main problems of skeletal maturation assessment and the
sources of possible bias (90, 91, 92). Therefore, it is mandatory that one
is acquainted with the specific qualities of the BA determination
method used.
B. Computed assisted skeletal age-scoring systems
As stated above, estimates of BA do not advance smoothly as the
child matures but in a saltatory fashion. In the TW2 system, a
difference of one stage in the rating of a particular bone may result
in an increase of 0.3 years in BA. In actuality, skeletal maturity
will advance gradually. To diminish the errors in the interpretation of
maturity and to improve BA ratings, the TW2 system has been transformed
recently by the original author into a computerized image analysis
system using a continuous scale Computer-Assisted Skeletal Age System:
CASAS (93, 94). So far, a limited number of studies have been performed
on the reliability and validity of CASAS in healthy children and in
children with tall stature (95, 96, 97). Results indicate that reliability
of the CASAS ratings is extremely high, both within and across
operators. Moreover, in longitudinal series, BA does advance far more
smoothly compared with manual scores. With regard to children with tall
stature, CASAS was found quite applicable. The CASAS method, however,
is not without drawbacks and is still, to some extent, user dependent.
Further developments are needed to improve these aspects.
C. Accuracy of height prediction
Prediction methods that have survived the tests of clinical
usefulness are those that incorporate a multitude of variables relating
to adult height and maturity and that are sensitive in their assessment
of childhood maturity (82). Most prediction methods are based on growth
data of unselected normally growing children. Therefore, when applied
to children with tall stature, critical appraisal of their qualities is
required. Knowledge concerning the specific advantages and
disadvantages of the various methods is of utmost importance
since it may influence possible therapeutic intervention.
Thus far, only a limited number of studies have been performed testing
the reliability of height prediction methods in large groups of
untreated children with tall stature. The accuracy of height prediction
may be expressed mathematically as the difference between predicted
adult height and actual adult height. In this way, positive values
indicate overestimation, and negative values reflect
underestimation of the final adult height. Absolute errors demonstrate
the methods overall predictive error and is not influenced by over-
or underestimation.
Table 3
summarizes the accuracy of
various prediction methods in boys with tall stature
(98, 99, 100, 101). The systematic tendency of the prediction methods to over-
or underestimate final adult height are not consistent. Variation in
initial clinical data (CA and BA) and time definition of reaching adult
height may account for this inconsistency. In general, however, the
method of Bayley-Pinneau tends to overestimate final height, whereas
the method of Tanner-Whitehouse slightly under- or overestimates final
height. Joss et al. (102) described a systematic
overprediction of the Bayley-Pinneau technique in a study of 32 tall
boys. In addition, they reported a systematic overprediction using the
Tanner-Whitehouse method, which was even more pronounced at an older
BA. Some investigators have used repeated predictions in the same
subject for accuracy assessment. This may have induced bias in reported
means and/or standard deviations of the errors of prediction. When the
group of patients was divided into age-specific subgroups it appeared
that with increasing age both methods became more accurate in
predicting adult height (100, 101). In our study the Index of Potential
Height (IPH) based on the BA of Greulich and Pyle was found to be the
most reliable method as it showed the lowest mean error and mean
absolute error, -0.1 (2.9) cm and 2.3 (1.8) cm, respectively
(101). The IPH is based on the assumption that the height
SD scores for BA [rather than for chronological age (CA)]
remains constant up to final height.
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Table 3. Mean error of prediction (cm) of the Bayley-Pinneau
and Tanner-Whitehouse method in untreated constitutionally tall boys
(prediction minus actual height)
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The accuracy of height prediction methods in girls with tall
stature is given in Table 4
(64, 101, 103, 104, 105, 106, 107, 108, 109). Again, inconsistency is present in reported errors of
prediction, probably due to differences in initial clinical data and
timing of adult height assessment. Nevertheless, the mean errors are
found to be rather small, indicating that height prediction in tall
girls is quite accurate regardless of which method is used. As in boys,
predicting adult height became more accurate with increasing age (101).
The mean absolute errors were also small, a confirmation of
their reliability. It seems that there is no best prediction method
in tall girls; the choice of method for use in daily practice may
therefore depend on the preference and experience of the clinician.
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Table 4. Mean error of prediction (cm) of the Bayley-Pinneau
and Tanner-Whitehouse method in untreated constitutionally tall girls
(prediction minus actual height)
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D. New prediction equations in constitutionally tall children
As stated above, for children growing at the upper extremes of
normal, i.e., beyond +2 SD above the mean of the
normal population, it seems far better to use prediction models based
on growth data derived from a sample of tall children. For this reason
Tanner and co-workers revised their original equations (Mark 1) (79) by
including numbers of very tall (and very short) children in the new
source sample in the standardizing group (Mark 2) (80). Unfortunately,
only tall girls had been included. This might explain the finding of
Cameron et al. (110) that the accuracy of prediction in tall
boys did not improve comparing the older TW Mark 1 method with the
revised TW Mark 2 method.
To improve height prediction in children with constitutionally tall
stature, we developed regression equations based on growth data derived
from a sample of untreated tall children (55 boys/88 girls) (111).
Since the quality of a regression model is reflected in its residual
standard deviation (RSD), the smaller the RSD the better the model
predicts the dependent variable (final height) by the combination of
predictor variables. In our newly developed prediction equations the
RSD was 2.5 cm for both boys and girls (see Table 5
). This implies that about 95% of the
predictions lie within approximately 5 cm of the real value (± 2 RSD).
From a clinical point of view, this inaccuracy is quite acceptable. In
comparison, Tanner et al. (79) reported RSD values up to 4.1
cm in boys and 3.6 cm in girls for the same age ranges. The prediction
equations were tested on a separate sample of 32 tall children (16
boys/16 girls) and compared with other prediction techniques including
the TW Mark 2 and Bayley-Pinneau method. The absolute errors of our
prediction equations were smaller (though not reaching statistical
significance) than the TW Mark 2 method and the Bayley-Pinneau
technique, indicating less variability. These results give support to
the idea that height prognosis in children with excessive growth is
more accurate when based on growth data derived from tall children.
In conclusion, although prediction techniques may have small mean
errors of prediction, it must be emphasized that considerable errors in
height prognosis may be made in individual cases. This is reflected by
the presence of the relatively large SDs of the mean errors
of the prediction method applied. It is preferable, therefore, to give
predicted adult height as a height with a confidence limit (using the
residual SDs of the prediction technique for calculation).
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VI. Treatment of CTS: General Concepts
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Treatment of tall stature is generally based on psychological
grounds. From a strict medical point of view, there is no reason for
treatment. Therefore, the validity and necessity for treatment are
questionable. Although psychosocial factors form the main reason for
treatment, extensive psychological investigation before or during
height reductive therapy has never been performed. Nevertheless,
psychological problems in tall adolescent girls and boys have been
recognized by pediatricians and endocrinologists (112, 113, 114, 115). A commonly
voiced concern is that these children feel different from their peers
and that they are subject to hurtful remarks about their height. As a
consequence, coping mechanisms such as kyphotic posture, social
withdrawal, and even depression have been observed. Fear about future
compatible partners (especially in girls) and career planning are also
frequently reported problems (112, 113, 114, 115). Practical problems for
adolescents and adults alike might arise concerning clothing and shoes.
Concurrent orthopedic problems, such as kyphosis or scoliosis, could
make treatment desirable for purely mechanical reasons. A study of
determinants of future trunk abnormalities in a cohort of 11-yr-old
schoolchildren suggested that in addition to the onset of the
adolescent growth spurt and the menarche, tall stature was positively
associated with the incidence of adolescent idiopathic scoliosis and
trunk abnormalities (116, 117).
Sex steroids have been used in the treatment of tall boys and girls
since the late 1950s. The basis for the use of sex hormones to limit
adult height came from observations in children with (pseudo-)
precocious puberty. These children show early closure of the epiphyses
due to premature production of gonadal steroids, which limits their
eventual adult height (118, 119).
Studies mainly in children with gonadal dysgenesis have suggested a
biphasic dose-dependent effect of estrogens on growth rate, low dose
having a stimulatory and high dose an inhibitory effect (36, 120, 121).
Furthermore, it has been demonstrated that the administration of high
doses of gonadal steroids, specifically estrogens, accelerate bone
maturation (98, 99, 103, 104, 112, 122, 123, 124, 125). Since the first study in
1956, many reports have appeared describing the height-reducing effect
of administration of high doses of sex hormones in girls (64, 103, 104, 105, 106, 107, 108, 109, 112, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131) and in boys (98, 99, 132).
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VII. Treatment of Constitutionally Tall Boys
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A. T treatment modalities
The effect of treatment with supraphysiological doses of T in
reducing adult height in boys appears to be different from the effect
of high doses of estrogens in girls. In T-treated tall boys, height
velocity is not decreased and even increased in the early stages of
puberty, whereas in estrogen-treated girls a decrease in growth
velocity is observed (62).
It is generally agreed that the steroid hormone effects on bone
maturation are due to an indirect action mediated by the GH/IGF-I axis
combined with a direct effect at tissue level after metabolic
conversion into estrogens (48).
The choice of the androgen preparation is unambiguous. Natural
compounds are preferred over 17-alkylated compounds as it has been
observed that the latter may cause cholestasis and hepatic tumors and
may negatively influence lipoprotein levels (115). The doses of the
long-acting T esters (such as T propionate, enanthate, and decanuate)
used in most studies are about 500 mg/m2/month, which
correspond to roughly 4 times the normal T production rate of adult men
or to about 810 times that of early adolescence. In clinical
practice, two weekly im injections of 500 mg or 250 mg once a week are
used. Whether such high doses are really necessary to obtain a maximum
effect on bone maturation is not known. However, treatment with T at a
mean dosage of 265 mg/m2/month resulted in a lower BA
velocity and thereby less reduction of adult height in a small group of
tall patients with hypogonadotropic hypogonadism (98). Theoretically,
an alternative treatment modality is testosterone undecanoate.
Testosterone undecanoate in oleic acid is administered orally and is
absorbed preferentially through the lymphatics into the bloodstream
bypassing first-phase degradation in the liver (133). However, dose
frequency is 23 times a day, and circulating blood levels tend to
vary substantially (134). Dose finding studies for CTS treatment have
not been performed.
B. Height reduction
The uncorrected effect of height reductive therapy,
i.e., height prediction minus achieved adult height, varies
with the prediction method applied. Since every single prediction
method has its own prediction error, the mean effect may be
corrected by subtraction of the corresponding mean prediction
errors (98, 99, 132) (see Table 6
). In
our own studies the Bayley-Pinneau prediction showed the
greatest mean corrected effect of 2.0 cm, while the IPH, being the
most accurate method, calculated a mean corrected effect of only
0.6 cm (101). An important finding, however, was that at the time of
referral the control groups (tall boys and girls) were significantly
different from children who had received sex hormone therapy. The
proper net treatment effect on final height was calculated by
multiple linear regression analysis adjusting for differences in age,
BA, and height prediction between treated and untreated children. The
mean adjusted effect for the various prediction methods varied from
-1.7 to +0.7 cm in boys. There was, however, a marked variation in the
individual height-reducing effect, ranging from -2.6 to +15.8 cm.
Figure 1
shows the adjusted effect of
therapy according to the IPH-Greulich-Pyle prediction and its
95% confidence interval.

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Figure 1. Adjusted effect of androgen therapy. The effect of
therapy was calculated by multiple regression analysis using final
height as dependent variable and treatment, and CA, BA, and height
prediction (and their interactions) as independent variables. Using the
height prediction according to the index of potential height for bone
age, the estimated treatment effect was a linear function related to BA
(Greulich and Pyle) in the form: Effect (cm) = 44.193.15
x BA (yr). The solid dots () represent all patients
with a given bone age, and the open triangles ( )
represent the 95% confidence interval of the calculated adjusted
effect. [Reproduced with permission from W. J. de Waal et
al.: J Clin Endocrinol Metab 81:12061216,
1996 (101 ). © The Endocrine Society.]
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These outcomes are clearly less than the corrected reductions of
4.77.5 cm previously reported (98, 99, 100, 132). In addition to the
variability in adult height prediction methods as discussed above,
these conflicting results may be due to differences in study design,
comparability of the control group, inclusion criteria (such as age and
BA at start of therapy), and therapeutic regimen. Furthermore,
differences in CA at the time of final adult height was measured, and
differences in BA at the time of cessation of therapy are important
contributing factors.
It has been clearly shown that height reduction was dependent on the BA
at start of therapy: height reduction was more pronounced when
treatment was started at a younger BA (100, 101, 132). However, an
important issue that caused a significant reduction in the
height-limiting effect was the observation of a marked additional
posttreatment growth after cessation of therapy. This posttreatment
growth might partly be explained by late-pubertal completion of spinal
growth. On the other hand, the additional growth could result from the
fact that treatment had been stopped before complete closure of the
epiphyses. A significant negative relationship between posttreatment
growth and BA at the time of stopping therapy (r =
-0.53; P < 0.001) was observed (101). The latter
contrasts with the opinion of Brämswig and co-workers (132), who
advocated short-term therapy and reported significant height reduction
(uncorrected: 7.6 cm) with a mean BA (SD) of 15.3(0.8) yr
at the time of stopping therapy. However, these results seem too
optimistic, since final height assessment was performed at a relatively
young mean (bone) age. Moreover, others failed to show any height
reducing effect using the same therapeutic strategy, but with
assessment of final height at a definite later point in time (135).
As illustrated in Fig. 1
, when therapy was started at a BA of 14 yr or
older, adult final height significantly exceeded height prognosis at
the time of start of treatment. This suggests that treatment had
resulted in induction rather than reduction of growth.
C. Effects on gonadal function
High doses of T induce suppression of the
hypothalamo-pituitary-gonadal axis (113, 136). Contraceptive studies in
adult men have shown that androgen-induced suppression of gonadotropins
and of spermatogenesis is reversible (137, 138). However, extrapolation
of these data to the management of tall stature in pubertal boys must
be viewed with caution since factors that regulate spermatogenesis in
normally functioning adult testes may not be the same as during puberty
(139). Androgen therapy in tall boys is usually initiated at the first
signs of puberty, and it is in this peripubertal period that important
maturational changes take place in the testis (139, 140, 141, 142, 143, 144). Influenced by
complex hormonal actions, these maturational processes eventually lead
to initiation of spermatogenesis. Onset of spermatogenesis (spermarche)
as detected by urine analysis (spermuria) appears to be an early
pubertal event: the median age of spermarche has been estimated to be
1314 yr (145, 146, 147, 148). In addition, it is noteworthy that administration
of T esters at high doses may cause morphological and cytological
changes, as shown in rat and human adult testes (149, 150, 151).
1. Plasma hormone levels. High T levels are obtained during
treatment with supraphysiological doses of androgens suppressing the
hypothalamo-pituitary-gonadal axis (152).
Zachmann, Prader, and co-workers (98, 113) reported a slow recovery of
pituitary gonadotropins during LHRH-stimulation tests after
discontinuation of T therapy. Brämswig et al. (136)
demonstrated normalization of gonadotropin levels in 100 tall boys
after discontinuation of treatment with follow-up periods up to 48
months, although transient hypergonadotropic LH- and FSH- secretory
patterns were observed. In a recently published study by the same group
(153), hormonal levels and testicular function were evaluated after a
follow-up period of approximately 10 yr and compared with normal
volunteers. Mean values of LH, FSH, PRL, T, estradiol, and sex
hormone-binding globulin were in the normal range in both groups. T was
lower and FSH was higher in treated tall men compared with volunteers,
but the only statistically significant difference was for T. We
observed different levels of gonadotropins in previously treated tall
men compared with controls (tall and normal men) (154).
Androgen-treated tall men had significantly higher FSH levels compared
with controls. Levels of plasma hormones were not significantly
correlated with parameters of sperm quality; however, we observed
significant negative correlations between plasma FSH levels and sperm
concentration as well as the age at start of therapy in the
androgen-treated men. We speculate that the higher levels of FSH may
reflect intratesticular changes due to androgen treatment received
during a period of testicular maturation especially during the earlier
pubertal stages (155). These increased FSH levels may compensate for
partially disturbed germinal function to maintain normal sperm quality
(156). In a subgroup of previously treated and untreated men, we also
measured inhibin B, which probably is a more direct marker of
spermatogenesis than FSH (157). We found similar levels, well within
the normal range (F. H. De Jong and W. J. De Waal,
unpublished results). On the other hand, the difference in gonadotropin
levels may also reflect a change in responsiveness at the
hypothalamo-pituitary level (136).
2. Testicular volume. Treatment with high doses of androgens
induces reduction in testicular volume in adult men (158) as well as in
tall adolescent boys (98, 99, 113). This implies major intratesticular
changes during therapy such as a decrease in seminiferous tubule size
(149, 150). These processes are likely to be reversible since
testicular volume normalizes after discontinuation of therapy as shown
in several studies (98, 99, 113, 158). This is in contrast to the
observations of Willig et al. (159, 160), who reported
significantly smaller testicular sizes in previously treated men. In
contrast, in our studies at a mean follow-up period of 8 yr after
cessation of treatment, there was no difference in mean testicular
volume between treated and untreated tall men (154).
3. Sperm quality. When sperm quality is evaluated, one must be
aware of the normal distribution in the population as well as of
confounding factors interfering with parameters of sperm quality. It is
well established that varicocele (161, 162, 163, 164), smoking (165), sexually
transmitted disease (166), and cryptorchidism (167) are likely to
affect sperm quality and/or plasma hormone levels. Semen analysis in
our study of previously androgen-treated men showed that sperm quality
was comparable with a control group of untreated tall men, even after
correction for the above mentioned possible interfering conditions,
after a mean follow-up period of 8 yr. These findings are in agreement
with the experiences reported by Zachmann and Prader and co-workers
(98, 113). In contrast, Willig and co-workers (159, 160) found
significantly reduced sperm concentrations in previously treated tall
men compared with controls. Their control group, however, showed a
relative high mean value of sperm concentration of 120.2 x
10'6/ml, almost twice as high as values found in the normal population
at present (168, 169). Their treated group showed a mean sperm
concentration of 63.4 x 10'6/ml, which is comparable with values
found in our study (154). It is possible that differences in
patient selection, semen analysis methodology, and treatment regimens
may account for the observed differences. In addition, the extent to
which interfering conditions are present may cause important bias as
well. In a recent report Lemcke and co-workers (153) showed that 10 yr
after T treatment, none of the tall men had azoospermia, and the mean
ejaculate parameters were in the normal range or only slightly
subnormal. Overall, seminal parameters of T-treated tall men were
slightly, but not significantly, lower compared with normal statured
volunteers. Interestingly, they found a significantly higher prevalence
of varicocele and maldescended testes in the tall men compared with
their control group of normal volunteers (153). They surmised that
varicocele and maldescended testes, rather than T treatment, caused the
somewhat lower semen quality in the tall men. In our studies in treated
and untreated tall men, we observed an overall prevalence of varicocele
of 42% (12% subclinical and 30% clinical) (154). This would suggest
that varicocele occurs more often than reported in the normal
population (12.425.8%) (170, 171, 172). A relationship to androgen
treatment is unlikely since no difference in the prevalence of
varicocele was observed between androgen-treated men and controls. One
could speculate on the impact of stature on the pathogenesis of
varicocele (153, 154).
4. Pregnancy/paternity. Thus far, only casuistic and exclusive
female data have been available on successful pregnancies after
height-reductive therapy. At the time of our follow-up studies five of
the 43 androgen-treated men and six of the 30 untreated tall men had
fathered one or more children (154). All 11 men reported that pregnancy
had occurred in their partners after less than 1 yr of unprotected
coitus. Two other pregnancies, fathered by a previously treated man and
a control, respectively, ended in spontaneous abortion. These
very limited numbers do not allow any further conclusions.
D. Other clinical effects
Many patients experience side effects during therapy (98, 99, 113, 132, 173, 174). Most of these, however, are mild and transient (see
Table 7
). In some patients, slight to
moderate edema, notably in the pretibial or malleolar area, was
associated with marked weight gain during the first 6 months of
treatment. This indicates that the early gain in weight is not only due
to protein anabolism but also to water retention (98). Acne was by far
the most reported side effect (98, 99, 175). Occasionally acne
fulminans has been reported and necessitated discontinuation of therapy
(173, 176). A causal relationship with androgen therapy is likely as
shown by Fyrand et al. (177). Hinkel et al. (178)
investigated the effects of high doses of androgens on lipoproteins
during and after the cessation of therapy. Although during treatment a
significant fall of triglycerides and HDL was observed, all values
normalized after the end of treatment (178). In our studies,
gynecomastia occurred in 13% of the cases. Since gynecomastia is
rather prevalent in population studies in pubertal boys (179), it is
difficult to say whether the condition had increased. One would expect
that treatment would have effects on sexuality (sex interest,
masturbation). Although in one study a marked increase of sexuality in
younger, but not in older patients, was noted, it never exceeded the
normal range seen in adolescence (98). Treatment with
supraphysiological doses of T were not shown to provoke aggressive
behavior in adolescents or young adults (180, 181).
 |
VIII. Estrogen Treatment in Tall Girls
|
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A. Estrogen treatment modalities
In 1956 Goldzieher introduced estrogen as a treatment of excessive
growth in adolescent girls (182). Since then, many reports have
appeared describing the height-reducing effect of high-dose estrogen
therapy in tall girls (64, 101, 103, 104, 105, 106, 107, 108, 109, 112, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131). Many
investigators, mainly in the United States, treated excessively tall
girls with conjugated estrogens (114). In Western Europe, others used
ethinyl estradiol (EE) in varying dosages usually combined with a
progestogen 710 days each month to induce cyclic bleeding and to
avoid overstimulation of the endometrium (103, 107, 131).
Norethisterone, medroxyprogesterone, and dydrogesterone have been used
as progestagen, 510 mg/day. The two last preparations, in particular,
show low to absent androgenic effects (183). In the past, estrogens
have been administered in the form of stilbestrol, 15 mg per day
(112, 113, 182, 184). However, since it has been reported to cause
vaginal cancer in the female offspring of women treated during
pregnancy (185, 186), stilbestrol is not a suitable treatment modality.
It has the additional disadvantage of inducing marked pigmentation and
hyperkeratosis of the nipple. Estradiol esters, such as
estradiol-valerate and -benzoate, have been used since they were
considered to be more physiological than oral ethinyl estradiol
(EE) or conjugated estrogens (113, 187). A disadvantage is that three
injections per cycle are required. Considering all advantages and
disadvantages, it appears that EE is the preparation of choice, since
the dose is standardized, administration is easy, and side effects are
not more marked or frequent than with any other preparation (103).
Whether the estrogens are given continuously or cyclically seems to be
of minor importance for the effect on height or for the resumption of
regular menstrual cycles after discontinuation of treatment (103). It
seems that the pituitary-gonadal axis tolerates continuous therapy for
a period of 12 yr very well. In the 1960s most practitioners used 500
µg EE; in the 1970s 200300 µg were used, and in the 19801990s a
dosage of 100 µg/day was claimed to be sufficient (101, 106, 107, 109, 113, 114, 125, 130, 131, 183, 188, 189, 190, 191). Whether even lower
dosages (e.g., 35 µg daily) are equally effective remains
to be assessed in a prospective clinical trial (131).
B. Height reduction
Studies on the effect of height reduction in tall girls have shown
various results using different prediction models within the same study
population (104, 105, 107, 108, 109, 124, 127, 129). The mean calculated
effect of therapy is corrected by subtracting the systematic
prediction error, as has been commonly reported in the literature. The
mean reported height reduction (corrected and uncorrected) in girls
with CTS ranged from 2.1 to 10 cm (64, 101, 103, 104, 105, 106, 107, 108, 109, 112, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131)
(see Table 8
). A clear comparison,
however, is hampered by differences in initial clinical data
(especially CA and BA), duration of treatment, therapeutic regimen
(different doses and estrogen preparations), and the point in time of
final height assessment. Concerning the latter, De Waal et
al. (101) observed a mean (SD) additional growth of
2.7 (1.1) cm after cessation of therapy, which is of the same order of
magnitude as in boys (107, 123, 127). The cause of the observed
additional growth is not quite clear. It could be explained by
cessation of therapy before complete closure of the epiphyses. In
addition, it is plausible that part of the remaining posttreatment
growth reflects additional spinal growth.
As discussed earlier, evaluating the effect of sex steroid treatment
after correction for the mean errors of the separate prediction
methods might induce bias. To calculate the net treatment effect,
multiple regression analysis has been used while adjusting for
differences in age, BA, and height prediction between treated and
untreated children. The mean adjusted effect for the various prediction
methods varied from 1.1 to 2.4 cm and ranged from -2.6 to 6.2 cm in
girls (101). These mean results are less than previously claimed (64, 103, 104, 105, 106, 107, 108, 109, 112, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131), probably due to differences in statistical
approach and study design, as explained above. Various studies show (as
illustrated in Fig. 2
) that the effect of treatment
was more pronounced when treatment had been started at a younger BA
(105, 108, 112, 123, 130, 131). However, others did not find such a
relationship (103).

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Figure 2. Adjusted effect of estrogen therapy. The effect of
therapy was calculated by multiple regression analysis using final
height as dependent variable and treatment, and CA, BA, height
prediction, and menarche (0 - no; 1 - yes) (and their interactions)
as independent variables. Using the Bayley-Pinneau prediction method,
the estimated treatment effect was a linear function related to BA
(Greulich and Pyle) in the form: effect (cm = 20.22 x 1.44 x BA
(yr.). The solid dots () represent all patients with
a given bone age and the open triangles ( ) represent
the 95% confidence interval of the calculated adjusted effect.
[Reproduced with permission from W. J. de Waal et al.:
J Clin Endocrinol Metab 81:12061216, 1996 (101 ). © The
Endocrine Society.]
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Results are inconsistent concerning whether or not premenarcheal girls
may experience more height reduction compared with postmenarcheal
girls. Some reports are in favor of this finding (109, 122, 123, 125)
while others observed no difference (103, 107, 128, 130). In our study
(101), premenarcheal girls seem to benefit more from therapy than
postmenarcheal girls. However, this was likely to be due to the
differences in CA between the groups since we found no additional
effect of menarche on CA explaining the variability in the effect of
treatment. This may, at least in part, explain the conflicting results.
C. Effects on gonadal function
1. The hypothalamo-pituitary-gonadal axis and menstrual
cycles. Suppression of the hypothalamo-pituitary-gonadal axis
induced by pharmacological doses of estrogens via a negative feedback
mechanism was found to be reversible (136, 192). Hanker et
al. (192) assessed the functional state of the
hypothalamo-pituitary axis by standardized LHRH testing in 16 tall
girls treated with 300 µg EE daily for 726 months. While absent LH
responses were observed in all girls immediately after therapy was
stopped, 4 to 8 weeks later the LH responses had normalized in 13 girls
and 12 weeks after therapy in 14 girls. All girls experienced
spontaneous menstrual bleeding within 3 to 22 weeks after termination
of therapy. The same was observed in most later follow-up studies in
which first menstruation was reported within 16 months after
cessation of treatment, in most cases even after the first month (103, 114, 127, 130). Amenorrhea of longer than 6 months after cessation of
height-reductive therapy was reported in about 5% of the cases (175).
The incidence of prolonged amenorrhea after cessation of oral
anticonceptive therapy is about 0.5% (193). In addition, the overall
prevalence of secondary amenorrhea of more than 6 months in women aged
1534 yr is about 1.3% (194). This may suggest an increase of
amenorrhea after height-reductive therapy. It should be noted, however,
that there are no convincing data that use of oral contraceptives (OCs)
is causally related to amenorrhea and that other risk factors for
amenorrhea, such as smoking, nutrition, and exercise, were not
adequately investigated (193, 195). No differences were found in
menstrual cycle characteristics between previously treated and
untreated tall women after a mean follow-up period of almost 11 yr
(175).
2. Pregnancy. In girls, pregnancy, which is the ultimate
proof of complete reversibility of hypothalamo-gonadal suppression,
has been reported in various single cases (112, 113, 127, 128, 130, 131, 189). In our own study, information on a total of 63 pregnancies
was obtained from 40 previously treated tall women. No distinct
differences in details and outcome of pregnancies between treated and
untreated tall women were found (175). These results indicate that
long-term effects of high doses of estrogens on fertility are unlikely.
Although a mean follow-up period of 10 yr is still too short to draw
definite conclusions, there is no clear evidence that treatment with
high doses of sex steroids does induce harmful effects on reproductive
function in tall girls.
D. Other adverse effects
In most studies, unwanted side effects have been reported only
during treatment or shortly after discontinuation of therapy (109, 112, 113, 127, 128, 130, 131, 183, 189, 196, 197). Most side effects were
found to be mild and reversible (see Table 9
). In a large retrospective study
short-term and long-term effects of high doses of estrogens in the
management of CTS were evaluated at a mean follow-up period of 10 yr
after discontinuation of height-reductive therapy. OCs were used by a
high proportion of previously estrogen-treated girls as well as
controls. An impressive bulk of data on the association between
long-term OC use and possible health risks (reviewed in Refs. 198, 199) form an excellent reflection of the prospective risk in
estrogen-treated girls. The proportion of OCs use and reported side
effects were not significantly different between estrogen-treated and
nontreated women. More than 70% of the estrogen-treated women had
experienced one or more side effects during therapy, such as weight
gain, headache, nausea, leg cramps at night, increased pigmentation of
areola and nipples, and vaginal discharge. Although most of them were
mild and transient, the adverse effects of estrogens occurred more
frequently during therapy than during OC use (175). This would suggest
a dose-dependent effect of estrogens on the incidence of adverse events
(107, 130).
Although hemostatic changes have been reported (196, 200, 201),
thrombosis is found to be a very uncommon side effect of
height-reductive therapy (112, 132, 196). Whenever thrombosis occurred
it usually coincided with other risk factors for thromboembolism such
as immobilization (202). Galactorrhea is an infrequent side effect of
estrogen therapy in tall girls (113, 123, 183). Hyperprolactinemia may
be more frequent but is reversible in most cases (Ref. 192 and M. C. A.
M. Houdijk and H. A. Delemarre-Van de Waal, submitted for publication).
The effect of high-dose estrogens on lipid metabolism was evaluated in
several studies (178, 204). The changes of serum lipids and
lipoproteins during estrogen therapy were reversible after cessation of
treatment.
Malignancy was not reported in our follow-up study (175). Although
there have been no reported cases of ovarian, uterine, vaginal, or
breast malignancies in girls treated for tall stature, the risk of
cancer in young women receiving estrogens remains uncertain. The
possibility of a dose-dependent effect and a relationship with OC use
at a young age and duration of OC use with increased risks of breast
cancer (205) point to the need for long-term follow-up of patients
treated with pharmacological doses of estrogens.
 |
IX. Alternative Treatment Modalities and Future Research
|
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An alternative strategy to limit growth in children with tall
stature utilizes interference in the regulation of GH secretion. It is
based on the assumption that tall stature is related to GH
hypersecretion. Bromocriptine therapy has been proposed as a means to
suppress endogenous GH secretion. Bromocriptine is a dopamine agonist
and inhibits GH secretion in patients with acromegaly by binding to
pituitary dopamine receptors (206). In the 1980s, studies on the
effectiveness of bromocriptine in reducing final adult height in
children with CTS revealed conflicting results. The studies of
Evain-Brion and colleagues (207, 208, 209, 210) reported marked decreases in
height prediction in a group of about 30 adolescents after a treatment
period of 915 months. It was stated that the reductive effect on
height prediction was mainly due to an increase in bone maturation
rather than a decrease in height velocity; IGF-I and IGF-II levels
remained unchanged. In contrast, other studies did not substantiate the
effect of bromocriptine treatment on height prediction or skeletal
maturation in children with tall stature (211, 212, 213). Recently, research
has focused on somatostatin analogs for the management of tall stature.
Somatostatin is a neurohormone produced at the hypothalamic level that
has potent inhibitory properties on GH release in the pituitary via the
vascular network of the portal system (214). Preliminary data revealed
an effective suppression of GH secretion in small groups of tall
children and a significant reduction in growth rate and predicted adult
height (215, 216, 217, 218). In addition, plasma IGF-I levels decreased whereas
bone maturation accelerated in many of the treated children (216). The
effect of somatostatin on bone maturation suggests that somatostatin
acts not only by systemic hormonal effects on GH and/or IGFs but also
by local regulatory effects on bone growth and metabolism. This
hypothesis is supported by the observation of Lamberts (219), who found
symmetrical bands of increased radioactivity by means of in
vivo somatostatin receptor-imaging techniques at the epiphyseal
surfaces of children with neuroblastoma. Final results on height
reduction by somatostatin therapy have not yet been established, and
the possibility of serious side effects such as gall stones must be
considered.
Strategies to limit final height of tall children have centered around
the peripubertal years. This is mainly due to the use of high doses of
sex steroids to advance skeletal maturation. Hindmarsh et
al. (218) suggested that in the management of children with tall
stature, attempts should be made to reduce the prepubertal contribution
to stature. Since prepubertal growth is largely GH dependent,
somatostatin analogs might be used to reduce the actual height from
which the pubertal growth spurt will commence. In addition, sex steroid
therapy may be applied as an adjuvant during puberty to optimize the
ultimate height-reducing effect. Other possibilities are low-dose sex
steroid treatment starting at an early prepubertal age (106), or
orthopedic modalities such as bilateral epiphysiodesis around the knee
(220) or femoral shortening (221).
 |
X. Conclusions and Recommendations
|
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Treatment of CTS is generally based on psychological grounds.
Children and adults with excessive growth may suffer considerably from
being much taller than their peers. Although psychosocial factors form
the main reason for treatment, extensive psychological investigation
before or during height-reductive therapy has never been performed.
There are no objective prospective data indicating lifelong
psychosocial damage as a result of tallness. In two retrospective
studies men and women previously treated with high doses of sex
steroids because of CTS showed no major psychological maladjustment
compared with tall controls (180, 181). Nevertheless, many tall
individuals experience practical problems concerning clothing and
shoes, are teased, and are subject to hurtful remarks and jokes about
their height. Thus, careful attention should be paid to the
psychosocial problems related to tallness especially in relation to the
sociocultural environment when considering treatment.
Prospective controlled studies that answer the main question of whether
treatment with pharmacological doses of sex steroids is effective in
reducing final height have never been performed. As claimed
effectiveness is based on height prediction, a critical appraisal of
the quality of the various prediction methods is in order. Height
prediction in tall girls is more accurate than in boys.
It is suggested that height prognosis in children with excessive growth
is more accurate when based on growth data derived from untreated tall
children (101). It must be emphasized that although prediction
techniques may have small mean errors of prediction, in individual
cases considerable errors in height prognosis may be made. This is
reflected by the presence of the relatively large SDs of
the mean errors of the prediction method applied (191). It is
preferable, therefore, to give predicted adult height as a height with
a confidence limit using the residual SDs of the prediction
technique for calculation (see Table 5
). Repeated measurements at
intervals of 46 months will improve the clinical relevance of the
prediction. Treatment with supraphysiological doses of sex steroids has
been advocated for final height reduction since 1950.
When the many reports in the literature on the height-limiting effect
of sex steroid treatment are analyzed, one may conclude that height
reduction is dependent on the BA at the time of start of treatment. In
our experience, tall girls benefit more from sex steroid therapy than
tall boys, but data from the literature are not consistent.
As shown in Figs. 1
and 2
, the period during which effective height
reduction is to be expected is quite limited. The upper limit of this
period is determined by BA (Greulich and Pyle) of <14 yr in
boys and of <13.514 yr in girls. The lower limit is determined by
psychosocial constraints, as treatment clearly induces puberty.
Posttreatment growth caused by cessation of treatment before complete
closure of the epiphyses may cause a significant reduction of the
height-limiting effect of treatment. The optimal dose of sex steroids
is not known. In the course of time the dosage of oral ethinyl
estradiol for girls has been reduced gradually from 500 µg/day to
100200 µg/day. In boys, long-acting T esters, 1000
mg/m2/month, is most often recommended administered ip once
per 1 or 2 wk. For late maturing individuals, it is advisable to
initially prescribe a reduced dose with subsequent gradual
increments.
To date, no evidence of long-term side effects of high doses of sex
steroids have been demonstrated after 810 yr. This limits the need
for a prospective trial to assess the effectiveness of a lower dosage
regimen. On the other hand, in view of a relationship with OC use at a
young age and duration of OC use with increased risks of breast cancer
(205), there is a need for long-term follow-up of individuals treated
with pharmacological doses of estrogens. Similarly, while no hard
evidence of testicular damage has been established after androgen
treatment in tall boys, the finding in one study of marginally elevated
FSH levels along with normal sperm counts, testicular volume, and
endocrinological parameters including inhibin B levels, warrants
further study.
In conclusion, it is recommended first to refer constitutionally tall
children in the late prepubertal period (810 yr) to secure proper
pretreatment evaluation of growth and bone maturation. Second, to
restrict treatment to excessive tallness or a very outspoken
professional desire where height forms a clear limitation
(e.g., pilot, ballet dancer). Third, treatment should be
initiated at an early bone age, psychosocial constraints
permitting. Treatment should not start before an age corresponding to
the 10th percentile of the first stage of pubertal development.
Moreover, although retrospective studies have not provided hard
evidence of testicular damage, it should be realized that in boys
androgen treatment might interfere with pubertal testicular
development. Finally, treatment should be continued until complete
closure of the epiphyses has been established radiologically.
In view of the crucial role of GH during the pubertal growth spurt, it
is tempting to speculate on other treatment modalities that might be as
effective or perhaps even more effective than the current practice.
There may be new ways of effectively suppressing GH secretion not only
by somatostatin analogs (223), but also by GHRH or GH
antagonists (224, 225, 226).
 |
Acknowledgments
|
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The authors thank Mrs. A. Oudesluys-Murphy for a careful
linguistic review of the manuscript and gratefully acknowledge the
expert bibliothecarial assistance of Mrs. M. L. van
Rooijen-Dekkers and the secretarial assistance of Mrs. A.
Visser-Vermeer.
 |
Footnotes
|
|---|
Address reprint requests to: Stenvert L. S. Drop, M.D., Ph.D., Division of Endocrinology, Sophia Childrens Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands. E-mail: drop{at}alkg.azr.nl
1 This study was supported by Stichting Kinderpostzegels, Leiden;
Stichting Menselijke Voortplanting, Rotterdam; and Sophia
Stichting voor Wetenschappelijk Onderzoek, Rotterdam. 
 |
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