EFFICACY
OF GROWTH HORMON THERAPY IN TURNER'S SYNDROME
EJ Gault & Dr MDC Donaldson, Department of Child Health,
University of Glasgow
INTRODUCTION
Turner’s syndrome (TS) affects approximately 1 in every
1900 live female births [1] and is caused by the loss or abnormality
of the second X chromosome in at least one major cell line in
the body.
The two principal features of the condition are short stature
and ovarian dysgenesis. Short stature is almost invariable, untreated
subjects achieving a final height approximately 21cm shorter than
the normal female population [2]. Ovarian failure occurs in the
great majority of girls so that oestrogen is required from adolescence
and throughout adulthood for the development of secondary sexual
characteristics and maintenance of bone and cardiac health. The
short stature and ovarian dysgenesis may be accompanied by a large
and variable number of additional features, including neck webbing,
ptosis, facial naevi, cubitus valgus, peripheral lymphoedema and
hyperconvex nails. Renal defects such as horseshoe kidney, left-sided
cardiac anomalies, thyroid dysfunction and autoimmune disorders
are more common in TS, as are middle ear anomalies, often resulting
in significant morbidity during childhood. The distribution of
intelligence in TS mirrors the normal distribution of the general
population. However, girls with TS can have specific cognitive
difficulties, in particular, with number work and visuo-spatial
tasks and these, coupled with a tendency towards high activity
levels and immature behaviour, can have educational and social
implications.
GROWTH HORMONE THERAPY
Short stature in TS results from impairment of all three phases
of the infancy-childhood-puberty model of growth. Mean length
at birth is reported as 0.5-1.0 standard deviation scores below
the population mean [3,4] and this deficit increases during infancy.
Growth rate continues to decline throughout childhood and, while
understanding of the precise mechanisms is incomplete, probably
results from an impaired response to growth hormone combined with
an underlying skeletal dysplasia. The pubertal growth spurt is
absent, reflecting the deficiency in ovarian oestrogen secretion,
as well as the inherent skeletal dysplasia.
Correcting short stature in TS has been a particular focus
of interest and research and, in particular, the benefits of growth
hormone (GH) therapy have been examined. It is extremely difficult
to quantify the social and psychological impact of short stature.
Speculating on the possible advantages afforded by extra centimetres
in adult height is highly subjective, particularly within the
context of a complex disorder such as TS. Attempts to examine
such abstract concepts are scarce, especially in the paediatric
field. However, the commitment shown by so many families to an
intensive treatment regime, often over a period of several years,
suggests that improved growth and height, whilst by no means the
sole concern, are greatly coveted. Whilst much more needs to be
done in assessing the impact of GH on quality of life (QoL), research,
to date, has focused on the impact on growth and final height
since these are readily measurable.
Biosynthetic GH has been widely available since 1985 and has been used extensively
to treat various growth disorders, including TS. Since girls with
TS do not have classic GH deficiency, interest has centred on
the use of doses larger than the 15 IU/m2/week used
to treat classical insufficiency. GH (prescribed in International
Units (IU) or milligrams (mg): 3 IU=1 mg), according to either
body surface area or body weight, is administered by subcutaneous
injection and has a very impressive safety record. Numerous studies
have shown the resultant augmentation in growth velocity and improvement
in final height [5-14], although with considerable variation (see
table). The impact of the adjunctive use of the anabolic steroid,
oxandrolone, and the timing of oestrogen therapy remain matters
for debate and these issues are currently being investigated by
the UK Turner Study: a prospective, collaborative, double-blind,
placebo controlled study into growth promoting treatments for
TS.
GAUGING RESPONSE TO TREATMENT
Whilst GH is known to augment height velocity in
growing girls, the ultimate measure of success in response to
growth promoting treatment is final height (FH), defined as height
velocity <0.5 cm per year with complete fusion of the epiphyses.
While it is impossible to accurately quantify the height "gained"
as a result of treatment in any given individual (since
their final untreated height can never be known), by comparing
FH in groups of treated girls with historical controls,
parental heights, the projected adult height (PAH) (see below)
and height predictions, the differences between actual and expected
FH can be identified. The following models can be used to calculate
expected FH, with the PAH method being the most favoured.
- historical controls: reference data from more than
15 countries are available and are summarised by Rochiccioli
et al [2]. Where possible, up-to-date reference data from the
same country of origin should be used to allow for any significant
geographic or demographic differences.
- parental height: the untreated adult height of most
girls with TS falls outwith their target range, therefore, a
FH within this range suggests that treatment has enhanced
growth.
- PAH: this method estimates adult height by extrapolating
from childhood measurements using either the regression equation
developed by Lyon et al [15] or reference data [15,16] which
assume that, if untreated, girls with TS will follow the same
height centile into adulthood. Height "gain" is expressed
as FH minus PAH.
- predicted height: various models have been developed
to predict adult height from bone age calculations, such as
Greulich and Pyle, Bailey Pinneau and Tanner and Whitehouse.
This model appears no more effective than PAH, however, and
the validity of using a method devised for normal children in
a group with a degree of skeletal dysplasia is questionable.
RESULTS
The many different GH regimes, along with the inconsistent use of anabolic
steroids and timing of pubertal induction, in various studies
make direct comparison of outcomes difficult. Reviews of the world-wide
literature have reported variable results [17,18], illustrated
by the following table published by Guyda in 1999 [18]. Although
results have varied from centre to centre, virtually all studies
have shown evidence of an increase in treated FH versus expected
untreated FH.
Table - Final height in Turner syndrome girls treated with GH
| Author (country) |
Yr |
N |
GH dose
(IU/kg/wk)
|
Age started
(yr)
|
FH
(cm)
|
PH
(cm)
|
FH - PH
(cm)
|
| Rochiccioli
(France) [11] |
1995 |
117 |
0.9 |
12.9 |
147.7 |
144.1 |
+3.6 |
| Massa
(Holland) [14] |
1995 |
45 |
0.8—1.2 |
|
152.3 |
149.7 |
+2.6 |
| Van
den Broeck (5 countries) [19] |
1995 |
78 |
0.5—1.0 |
12.9 |
150.7 |
147.8 |
+2.9 |
| Takano
(Japan) [7] |
1995 |
12 |
0.5 |
10.3 |
145.1 |
137.0 |
+8.1 |
| |
|
16 |
1.0 |
9.7 |
144.0 |
137.0 |
+7.0 |
| Heinrich
(Belgium) [12] |
1995 |
31 |
0.9 |
12.2 |
151.3 |
142.9 |
+8.4 |
| |
|
15 |
0.8 |
14.9 |
153.8 |
147.0 |
+6.8 |
| Taback
(Canada) [20] |
1996 |
17 |
0.9 |
12.4 |
148.0 |
148.2 |
-0.2 |
| Chu
(Scotland) [21] |
1997 |
26 |
0.5—1.0 |
12.5 |
142.6 |
142.0 |
+0.6 |
| Nilsson
(Sweden) [9] |
1996 |
44 |
0.7 |
12.2 |
152.0 |
146.0 |
+6.0 |
| Haeusler
(Austria) [22] |
1996 |
20 |
0.5—0.8 |
11.8 |
152.9 |
143.7 |
+9.2 |
| Rosenfeld
(U.S.) [10] |
1998 |
171 |
1.1 |
9.9 |
150.4 |
142.0 |
+8.4 |
| |
|
432 |
1.1 |
9.9 |
152.1 |
141.8 |
+10.3 |
| Plotnick
(U.S.) [6] |
1998 |
622 |
1.0 |
12.9 |
148.3 |
143.8 |
+6.4 |
| Carel
(France) [13] |
1998 |
17 |
0.93 |
10.2 |
148.3 |
143.1 |
+5.2 |
| |
|
12 |
2.14 |
11.0 |
155.3 |
144.7 |
+10.6 |
| Betts
(UK) [23] |
1999 |
52 |
0.8 |
10.7 |
150.85 |
146.75 |
+4.1 |
| Sas
(Holland) [24] |
1999 |
19 |
1.2 |
13.5 |
155.5 |
149.2 |
+6.3 |
| Dacou-Voutetakis
(Greece) [25] |
1999 |
356 |
0.7 |
11.5 |
146.1 |
145.0 |
+1.1 |
| Ranke
(43 countries) [26] |
1999 |
979 |
0.8 |
13.17 |
148.07 |
144.07 |
+6.77 |
| Total
or mean |
|
2217 |
0.5—2.1 |
11.8 |
150.0 |
144.3 |
+5.7 |
1 Received GH alone with
late introduction of oestrogen therapy.
2 Received GH plus oxandrolone at a dose of 0.0625 mg/kg/day
and late oestrogen therapy.
3 Received standard doses of GH of 0.9 IU/kg/wk; onset
at age 11 yr.
4 Received adapted doses of GH up to 2.1 IU/kg/wk; onset
at mean age of 10 yr for 4 yr, with late introduction of oestrogen
therapy.
5 Approximate as calculated from SD score (Turner specific)
provided by authors.
6 Duration of GH therapy was only 2.2 yr.
7 KIGS database: median values. Lyon height prediction
[15] indicated a gain of 6.7 cm. GH plus oxandrolone at a dose
of 0.05 mg/kg/day in 25% of patients and late oestrogen therapy
in all.
Thus, Guyda found a mean FH achievement of 150cm [18], compared
to an untreated mean FH reported elsewhere of 142.9cm [15]. Also,
Rosenfeld et al [10] reported a mean FH of 150.4cm, some 8.4cm
above the PAH, in a group of 17 girls treated with GH alone and
considers 150.0cm as a reasonable target for treatment. In Glasgow,
Scotland, we have found that 19 of 30 girls (63.3%) receiving
GH treatment and reaching near-final/final height since 1993 have
already exceeded this target of 150cm with a mean near-final/final
height of 150.6cm [new data, unpublished], see figure for comparison
with Scottish results reported by Chu et al [21]. When compared
with this earlier data, the Glasgow group exhibits a significantly
greater FH & `TS Ht SDS following growth promoting treatment.
It appears that, as more is learned about the optimal treatment
regime and therapy is consistently prescribed over a prolonged
period, height outcomes improve.
Figure — Near-final/Final heights attained by girls
with TS treated at the Royal Hospital for Sick Children in Glasgow,
1993-2000 (dark bars) compared with previous data from Scotland
1988-1993 (pale bars)[21]
While there is no doubt that the growth of groups of girls with TS is
improved by GH therapy, there is considerable individual
variation in response to treatment, with Guyda reporting minimum
FHs ranging from 131.5-145cm in five of the studies reviewed [18].
FACTORS POTENTIALLY AFFECTING RESPONSE
While the optimal treatment regime is, as yet, unknown, the following
factors have been identified as potential predictors of response
— the first, age at start at treatment, is emerging from
the literature as the primary predictive factor:
- age at start of treatment — retrospective reviews
in the US and the UK have found the best results are associated
with a younger age at the start of treatment [6,23].
- duration of treatment — a positive correlation between
FH and duration of treatment has been identified [6,11,26].
- dose of GH — a significantly greater growth rate has
been reported with higher doses [7,23]. Promising results have
been shown with doses ª58 IU/m2/week (@
2.1 IU/kg/wk) [8,13] although the long-term safety of such very
high doses requires further investigation.
- frequency of injections — the best responses have been
found with more injections per week [14,26].
- height at start of treatment — studies have found that
the tallest girls at the beginning of treatment achieve the
greatest FHs [11,14,19]. However, a negative correlation between
initial height and FH minus PAH [7,11,12,14,19] suggests that
the shortest girls benefit most from treatment.
- mid-parental height — those with tall parents appear
to reach the most favourable FHs, demonstrating the genetic
influence [6,11,26].
- bone age (BA) —a negative correlation has been found
between BA and FH-PAH [9,14,19,22] suggesting that as the skeletal
system matures, the benefits of GH therapy are reduced.
- compliance — family motivation and commitment are as
important in influencing response to treatment. None of the
above factors is relevant if treatment is not administered in
the first place.
NB the relative influence of the following factors on
FH remains unclear and both are currently under investigation
as part of the UK Turner Study.
- oxandrolone - used in combination with GH, this anabolic steroid
has been shown to increase growth velocity [9,10,22,27]. Its
impact, if any, on FH, however, remains a matter of debate.
- timing of oestrogen induction — opinion is divided as
to the optimal age at which to induce puberty. A recent study
found that the number of "oestrogen-free" years of
GH treatment was a significant factor in FH outcome [28].
CURRENT UK PRACTICE
Opinion as to best practice is constantly evolving and this is
illustrated by the changing pattern of GH use in the UK over the
past decade or so, reflecting the messages learned from previous
research. The mean age of starting treatment has fallen significantly
from 10.4 to 8.5 years. The starting dose has risen significantly
from 0.55 to 0.95 IU/kg/week (@ 15.4
to 26.6 IU/m_/wk) and the frequency of injections has increased
from 3 to 6/7 per week [19].
The regime currently considered "best practice" is
a dose of 30 IU/m2/week (@
1.0 IU/kg/week) in daily injections, beginning when height falls
below —2 SD or when the family identifies short stature as
a problem and preferably by 8 years of age.
CONCLUSIONS & RECOMMENDATIONS
There is a clear case for GH therapy in the treatment of TS.
Groups of girls do well, with an increase in growth and improvement
in final height and large-scale collaborative studies are needed
to examine the impact these have on QoL. Some individuals, however,
respond less well to treatment than others and the possible reasons
for this also require further investigation.
Questions remain over the best age at which to begin treatment
and while this is largely dependent on the age at diagnosis, it
would appear that starting earlier and, therefore, allowing a
longer period of treatment is most advantageous. In order for
girls to have, as has been recommended, a substantial number of
oestrogen-free years of GH treatment, beginning GH no later that
8 years of age is recommended, unless the individual is particularly
tall.
The optimal dose of GH has yet to be quantified but more rather
than less GH seems to result in the most favourable results. Clinicians
are cautioned, however, against adopting the high doses used by
the French and Dutch groups until further controlled investigation
is carried out and the safety issues examined. In addition, the
financial implications of adopting such large doses as standard
practice cannot be ignored. Intermittent therapy and incremental
dose increases, as a means of counteracting the waning effect
seen in response to GH over consecutive years of treatment, also
require further investigation.
Growth and height of the TS population is obviously improved
by GH therapy but many unanswered questions remain. In the meantime,
current UK best practice guidelines should be followed and any
changes to treatment strategy should be made within the context
of large scale, controlled, prospective studies.
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