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The Journal of Clinical Endocrinology & Metabolism 92(4):1195–1200
Copyright © 2007 by The Endocrine Society
doi: 10.1210/jc.2007-0167
APPROACH TO THE PATIENT
Approach to the Growth Hormone-Deficient Child
during Transition to Adulthood
Sally Radovick and Sara DiVall
Division of Pediatric Endocrinology, Department of Pediatrics, The Johns Hopkins University School of Medicine,
Baltimore, Maryland 21287
The observation that some adults with childhood-onset GH
deficiency have low bone mineral density, low lean body mass,
diminished quality of life, abnormal lipids, and impaired cardiac function, all of which may improve after treatment with
GH, has prompted pediatric endocrinologists to reevaluate
the practice of discontinuing GH in all patients after attainment of final adult height. The treatment of adolescents to
prevent the metabolic complications of GH deficiency is an
J
.D. is a 17-yr-old who has taken GH since age 5 for isolated
GH deficiency (GHD). At diagnosis, he had a delayed bone age, height less than 3rd percentile for his age,
growth velocity less than 3rd percentile, and an IGF-I level
of 25 ␮g/dl (182–780). An arginine-l-Dopa test resulted in a
GH peak of 1.3 ␮g/liter, a pituitary magnetic resonance
imaging was normal, and he did not develop evidence of
panhypopituitarism. He spontaneously entered puberty at
12.5 yr of age and it progressed normally. Six months ago, his
growth velocity had decreased to 3.5 cm/yr. At this visit, his
dose of GH was 0.42 mg/kg䡠wk (60 ␮g/kg䡠d). At previous
visits, the need to continue GH after achievement of final
adult height was discussed. Now he hopes that he is “done
growing” and is “tired of taking shots.” J.D.’s height is 170
cm (67 in., within his midparental height of 68 in.) and his
growth velocity is 2.2 cm/yr. His bone age is 17 yr, and his
thyroid, gonadal, and adrenal function tests are normal.
This case exemplifies a clinical situation that is relatively
new to pediatric endocrinologists: the reevaluation of GHD
after completion of growth and the consideration to treat
individuals with persistent deficiency. Research in the 1990s
demonstrated that some adults with GHD, particularly those
with childhood-onset GHD (CO-GHD), have lower bone
mineral density (BMD), lower lean body mass (LBM), lower
quality of life, higher cholesterol, and impaired cardiac function compared with normal adults. These effects of GHD in
Abbreviations: aBMD, Areal BMD; AO-GHD, adult-onset GHD;
BMD, bone mineral density; CO-GHD, childhood-onset GHD; GHD, GH
deficiency; iGHD, isolated GHD; ITT, insulin tolerance test; LBM, lean
body mass; MPHD, multiple pituitary hormone deficiencies; vBMD,
volumetric BMD.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
emerging practice. Studies addressing the evaluation and
care of adolescents during this period and the benefits of GH
in this setting are conflicting. Our approach in determining
which adolescents to retest, when and how to test for persistent GH deficiency, and which subjects to treat is discussed in
the context of available clinical data. (J Clin Endocrinol Metab
92: 1195–1200, 2007)
adults improve with GH treatment, and approval of GH for
adults was granted by the Food and Drug Administration in
1996. These findings, coupled with evidence that bone mineral accretion increases and body composition changes significantly after attainment of final adult height (1), prompted
pediatric endocrinologists to reevaluate their practice of discontinuing GH in all patients after attainment of final adult
height. The treatment of adolescents to prevent the metabolic
complications of GHD is an emerging practice, and studies
addressing the evaluation and care of adolescents during this
period and the benefits of GH in the transition period are
conflicting. In addition, young adults are geographically mobile and have frequent changes of providers, lack consistent
medical insurance, lack the experience to coordinate their
care, and may desire, as expressed by J.D., to discontinue
daily injections. Therefore, recommendations regarding
treatment must be individualized to the patient’s diagnosis
and risk factor profile, with the pediatric endocrinologist
providing rational evidence for treatment and guiding the
patient to a decision that is both beneficial and feasible.
The clinical decisions that the pediatric endocrinologist
must address in caring for adolescents like J.D. include: 1)
Who do I retest? 2) When do I retest? 3) How do I retest? and
4) Who do I consider treating and how do I treat him/her?
Our approach to each of these questions, and the clinical
evidence supporting our decisions, is detailed below. Children receiving GH for idiopathic short stature, Turner Syndrome, renal failure, and growth failure associated with
small for gestational age are usually GH sufficient on initial
testing and will not be included in this discussion.
Who Do We Retest?
We categorize GHD patients into groups that have a high,
moderate, or low probability of persistent GHD. The highprobability group includes children with confirmed organic
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Radovick and DiVall • GH Deficiency during Transition to Adulthood
pituitary disease causing multiple pituitary hormone deficiencies (MPHD) or isolated GHD (iGHD). Individuals with
confirmed mutations in genes controlling somatotroph development or GH gene expression (combined pituitary hormone deficiency) or midline or pituitary structural anomalies
fall into this category. The moderate-probability group includes children with idiopathic or acquired MPHD or acquired iGHD. This group includes children with congenital
MPHD of unknown etiology or with a history of pituitary
tumors, radiation, or surgery. The low-probability group
includes children with iGHD with normal or small pituitaries
on imaging studies. The positive predictive value for GHD
in adults with deficiencies of three pituitary hormones is
96%, and the value is 99% in adults with four pituitary
deficiencies (2). This is also true for adults with CO-GHD (3)
and in adolescents in the transition age with MPHD or a
structurally abnormal pituitary on repeat magnetic resonance imaging (4). Based upon these studies and personal
experience, children with a high probability of GHD will
have persistent GHD after provocative testing, and we do not
retest them (Fig. 1). Although it could be argued that all
children with MPHD are at high probability of persistent
GHD, we consider children with acquired MPHD as moderate probability because our experience is that some children with acquired MPHD do not meet the criteria for adult
GHD. This observation has been corroborated in a study of
adolescents with a history of cranial irradiation and GHD
where 50% did not meet the criteria for adult GHD on retesting (5). In addition, if MPHD is idiopathic, we feel that it
is necessary to confirm GHD before considering GH therapy
in the transition period. In this moderate-risk population, we
discontinue GH for 1 month and measure IGF-I. If the IGF-I
level is less than ⫺2 sd from the mean, we do not perform
GH provocative testing, as suggested by Hartman et al. (2).
High Probability
of persistent
GHD
Acquired/Congenital
MPHD or congenital
iGHD with structural
abnormalities or
confirmed mutations
FIG. 1. Algorithm detailing a method
to evaluate the GH status of transition
patients. *, Based upon consensus and
clinical practice guidelines (8, 9).
#
, Threshold values that achieve a sensitivity of 95% and specificity of 91–
92% for diagnosing GHD in adults
(12). §, Based upon data indicating
that patients with irradiation-induced MPHD can have hypothalamic
dysfunction causing GHD (15).
Multiple studies have shown that the incidence of adultonset GHD (AO-GHD) in adolescents with iGHD is much
lower than adolescents with MPHD; only 40 –75% of adolescents with iGHD have AO-GHD on retesting (3, 6, 7).
Therefore, we repeat provocative testing in all children with
iGHD or with only one other pituitary deficiency. A child
with iGHD and convincing evidence of pituitary malformation is categorized as having a high probability of persistent
GHD.
When Do We Retest?
Studies related to transitional care of GHD patients have
used different criteria to define achievement of near final
adult height and completion of skeletal growth. Most studies
have used a growth velocity of less than 2.5 cm/yr as criteria
for attainment of final height, with many retrospective studies using a growth velocity of less than 1 cm/yr. Few studies
have specified bone age criteria. In practice, if a child has
achieved 98 –99% of final adult height (bone age of 14 –15 in
girls or 16 –17 in boys) and has a growth velocity less than 3
cm/yr on adequate GH replacement, we consider reevaluation for transitional therapy.
In adolescents in whom retesting is deemed necessary, a
period off of GH is required before provocative testing. The
shortest time that an individual must be off without affecting
test results has not been defined. Consensus statements (8)
and clinical practice guidelines (9) suggest 1–3 months between GH discontinuation to retesting. Prospective studies
of adolescents in the transition period have generally retested in this time frame, and this is what we do in our
practice. Retesting after a longer period is reasonable, but we
find that adolescents are more likely to follow-up if we retest
soon after GH discontinuation. If a child has MPHD, we also
Moderate Probability of
persistent GHD
Low Probability of
persistent GHD
Acquired GHD from tumor, irradiation,
surgery; idiopathic MPHD
Idiopathic, isolated GHD
Off GH 1-3 months*
Low IGF-1
Off GH 1-3 months*
Normal IGF-1
GHRH-Arginine or Insulin Provocative Testing*
GH < 5.1 (Insulin)#
GH< 4.1 (GHRHArg)#
Persistent
GHD
GH < 10 GHRH-Arg
+ Mod. Probability§
Probable Persistent GHD
GH < 10 insulin,
GH<10 GHRH-Arg
+ low Probability
Partial GHD
or Normal
Radovick and DiVall • GH Deficiency during Transition to Adulthood
ensure that replacement of other hormones is sufficient before performing provocative testing.
Zucchini et al. (10) found that one third of children with
iGHD diagnosed before puberty had normal GH peaks when
retested in midpuberty. If GH was discontinued in the children who tested normally, final adult height was not significantly different than that in children with persistently
abnormal provocative tests who continued therapy. The authors were unable to formulate a prediction model of who
would have normal GH on retesting and subsequently
achieve a normal final height without GH treatment. Although these findings are intriguing, we do not think there
is adequate information to consider retesting children with
iGHD in midpuberty.
How Do We Test?
No studies have compared the reliability of all available
provocative tests for diagnosing persistent GHD in the transition population. The functional dynamics of GH secretion
are different in growing children and those who have
reached final adult height, (11), leading to different definitions of GHD in children and in adults and the use of the
adult definition of GHD in the transition population. The
gold standard test for detecting GHD in adults is insulininduced hypoglycemia (insulin tolerance test, ITT). This test
is recommended by consensus committees (8, 9) to reevaluate adolescents in the transition period. However, few pediatric endocrinologists use the ITT in the initial evaluation
of GHD because of the risk of hypoglycemic seizures. Therefore, many pediatric endocrinologists feel inadequately experienced and are unable to devote the resources to supervise
this procedure for testing in the transition period and employ
alternate protocols. The GHRH-arginine test is a reasonable
alternative to the ITT. In a comparative study of GH provocative tests, the GHRH-arginine test—at a different peak
GH threshold— had a sensitivity and specificity similar to
insulin-induced hypoglycemia (12). To achieve a sensitivity
of 95% and specificity of 92% for detecting GHD, the peak
threshold for GH in the ITT was 5.1 ␮g/liter and 4.1 ␮g/liter
for GHRH-arginine using a two-site immunochemiluminescent assay. To achieve a specificity of 95%, the threshold for
the ITT was 3.3 ␮g/liter and 1.5 ␮g/liter for the GHRHarginine test. Based upon these findings, we use the GHRHarginine test to retest adolescents at our institution.
A serum IGF-I level in a patient who has discontinued GH
treatment for at least a month may be helpful in identifying
persistent GHD. In a study of transition patients with MPHD
off GH treatment, Maghnie et al. (4) documented that the
serum IGF-I level may not fall to below normal levels until
6 months after GH is discontinued (4). In light of this finding
and the effects of nutrition and liver disease on IGF-I, we do
not make the diagnosis of persistent GHD or a normal GH
axis in a patient with iGHD based upon a serum IGF-I level
alone. In practice, we measure an IGF-I level after discontinuing GH in moderate-risk MPHD patients to identify
those who need repeat provocative testing.
Studies that have compared outcomes in persistently GHD
transition patients with and without therapy have used different GH peak thresholds to define GHD. In earlier studies,
J Clin Endocrinol Metab, April 2007, 92(4):1195–1200
1197
adults with a GH peak of less than 3.0 ␮g/liter on provocative testing were considered to have GHD (9, 13, 14). Recent
guidelines recommend a peak GH of 5.1 ␮g/liter in an ITT
or 4.1 ␮g/liter using GHRH-arginine testing to diagnose
GHD. Based on the study by Biller et al. (12), these cutoffs
have a sensitivity of 95% and specificity of 91% in detecting
GHD. Some investigators, citing evidence that GH secretion
in normal adolescents and young adults is higher than in
middle-aged or older adults (11), suggest that GHD adolescents may experience higher GH peaks than are seen in
deficient adults. No studies have compared outcomes for
GHD adolescents or adults based upon the different peak GH
values after provocative testing. In practice, pediatric and
adult endocrinologists do not make a diagnosis of GHD
based solely on results of GH provocative testing. For the
transition population, this practice will continue, considering
the lack of studies on this subject. Figure 1 outlines our
strategy for evaluating the GH status of patients in transition.
If an adolescent has a peak GH less than 4.1 ␮g/liter after
GHRH-arginine regardless of pretest probability, we consider him/her GHD. If an adolescent with a moderate probability of persistent GHD has a GH peak of less than 10
␮g/liter using the GHRH-arginine test, we consider this
probable persistent GHD. We do this because GHRH directly
stimulates the pituitary and may provide a falsely normal
GH peak in patients who have had irradiation or surgery to
the hypothalamus (15). If a patient has a GH peak less than
10.0 ␮g/liter on the ITT (independent of pretest probability),
or a GH peak less than 10 ␮g/liter on the GHRH-arginine test
and a low pretest probability of persistent GHD, we consider
them to have partial GHD.
Who Do We Consider Treating and How Do We
Treat?
Research to date has focused on the short-term consequences of discontinuing GH therapy and the efficacy of
continuing GH therapy in the transition population. LBM, fat
mass, BMD, and quality of life are the parameters most often
assessed.
In studies of adults with GHD, those with CO-GHD have
lower BMD, lower LBM, and higher fat mass than older
adults with AO-GHD (16, 17). It is postulated that the lack
of GH during the late teens and early twenties—a time when
bone and muscle mass continue to increase (1)— contributes
to the deterioration of these parameters in adults with COGHD. Several studies on this subject have yielded moderately convincing data on the changes in body composition in
patients with persistent GHD and the efficacy of GH in
preventing the changes, especially in those with MPHD. A
cohort of persistently GHD adolescents who discontinued
GH after attainment of final adult height had a significant
lack of increase in LBM, an increase in body fat, and adverse
changes in their lipid profiles compared with controls and
previously treated GH-sufficient adolescents (18). The same
cohort of 21 patients—16 with MPHD— experienced no improvement in strength compared with the other groups (19).
A different cohort of persistently GHD patients off GH for an
average of 1.5 yr after attainment of final adult height had
lower LBM and higher fat mass indices than a slightly older
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Radovick and DiVall • GH Deficiency during Transition to Adulthood
cohort of AO-GHD patients (20). The authors concluded that
the differences between the CO-GHD and AO-GHD group
were attributable to the lack of GH in the transition phase in
those with childhood onset of disease. This cohort also consisted of a majority of MPHD patients and, when a subset of
this cohort was randomized to restart GH at adult (12.5
␮g/kg䡠d) or near pediatric (25 ␮g/kg䡠d) doses, those receiving either dose of GH had a significant increase in LBM and
significant lack of increase in fat mass after 2 yr compared
with those who did not restart therapy (21). Similar results
were obtained in a prospective study of 19 persistently GHD
patients, 12 with MPHD, followed for 2 yr after attainment
of final adult height. A subset experienced 1 yr off therapy
then 1 yr on GH, whereas the remaining subjects received GH
for 1 yr. At 1 yr, the untreated group had a higher fat mass
than the treated group but similar LBM. After the subsequent
year of therapy, LBM increased significantly (22). In a recent
study comparing outcomes in treated persistently GHD adolescents, nontreated persistently GHD adolescents, and normal controls, no significant difference between the groups in
LBM, fat mass, or BMD was observed (23). The authors
speculated that the discrepant results were due to different
characteristics of the GHD populations. The studies showing
differences had GHD populations comprised of a majority of
MPHD patients, whereas the majority of the patients reported by Mauras et al. (23) had iGHD. The differences underlie the need to individualize recommendations.
Considering the inconsistent results from available studies, we consider the patient’s underlying diagnosis when
making treatment recommendations (Fig. 2). It is possible
that the differences in outcome between iGHD and MPHD
are due to the presence of other hormone deficiencies, underlying systemic disease, or variable levels of somatotroph
function in the two entities. Clearly more studies are needed
to investigate this issue.
Studies on the changes in BMD in transition patients with
persistent GHD have yielded even less clear results. The age
at which the BMD of persistent GHD young adults falls
below normal continues to be debated. In addition, most
studies have assessed BMD using areal measurements
(aBMD), which are dependent upon height. Volumetric BMD
(vBMD) determination may be more appropriate in this population (24). There is some evidence that adolescents with
persistent GHD, after discontinuing GH, achieve peak BMD
later and have lower peak lumbar spine vBMD than a GHsufficient control population (25). In the study by Baroncelli
et al. (25), the patient population also had a slightly lower
vBMD than the control population at final height, in contrast
to other studies in which lumbar vBMD at final height was
not different between GH-sufficient and GHD populations
(26 –28). Again, the discrepant results could be due to different study populations; the study by Baroncelli et al. followed only patients with persistent GHD, whereas the latter
studies included all patients on GH therapy as children, even
those who retested as GH sufficient. Shalet et al. (29), in the
same cohort of patients as reported by Attanasio and colleagues (20, 21), found a slight, but significantly greater increase in total body aBMD in the GH-treated vs. the untreated
GHD patients after 2 yr. Another study documented that
aBMD continues to accrue in untreated patients with persistent GHD after 2 yr at a slightly but significantly lower rate
(30) than treated patients of equivalent height. It is unknown
whether the two groups had lower baseline BMD than a
normal population. These results are in contrast to a recent
study comparing treated and untreated persistently GHD
patients with a control population. In this study, the spine
and total body aBMD were not significantly different at
baseline or after 2 yr in any of the study groups (23). Again,
the populations were different: the majority of patients in the
study by Drake et al. (30) had idiopathic or acquired MPHD,
Probable
GHD
GHD
MPHD
FIG. 2. Algorithm detailing an approach to treatment of transition patients with persistent GHD. *, Those at
high risk for metabolic complications
include patients with abnormal BMD,
high fat mass, and low LBM. **, Those
at low risk for metabolic complications
include patients with normal BMD, fat
mass, and LBM.
Partial GHD
or Normal
iGHD
MPHD
At high risk for
metabolic
consequences*
iGHD
At low risk for
metabolic
consequences**
Discuss with patient
risk/benefits of GH
continuation
Consider treatment
with GH 12 μg/kg/day
Monitor BMD, fat mass,
LBM, quality of life
Monitor
Clinically or
Discharge
Radovick and DiVall • GH Deficiency during Transition to Adulthood
whereas the majority of patients in the study by Mauras et al.
(23) had iGHD. All of these studies are short term, and, if any
effects on BMD were noted, they were small. Another complicating factor in these studies is that many MPHD patients
carry other risk factors for bone disease independent of GH
including a history of cancer, cancer treatment or irradiation,
hypogonadism, overtreatment with replacement glucocorticoids, or other systemic disease. Lastly, no studies to date
have been performed to investigate the effect of GH absence
in early adulthood on fracture risk later in life.
Quality of life assessments in adults with GHD show a
high degree of variability (9). Adults with CO-GHD generally do not have the same degree of impairment as those with
AO-GHD (16). Although no significant impairment in quality of life in GHD patients in the transition phase has been
reported, (31) quality of life changes that do occur after
discontinuing GH can be particularly troublesome to some
transition patients. If the patient would otherwise be categorized into an observational category (Fig. 2), we offer a
6-month trial of GH.
Because of the conflicting data on changes in LBM, fat
mass, BMD, and quality of life in patients during the transition phase, we tailor treatment to each patient’s diagnosis
and risk factor profile (Fig. 2). We then thoroughly discuss
the risks and variable benefits of therapy with the patient and
let the patient decide the most feasible treatment course. As
the effect on body composition of continuing GH in transition patients may not be appreciated by the patient, inclusion
of the newly independent adolescent in the treatment decision is important to ensure compliance and precise analysis
of treatment efficacy. Because GH therapy seems to positively affect body composition and vBMD in MPHD patients
with persistent GHD, we offer treatment to this population.
Although not specifically tested, it is logical to assume that
GH may also help the persistent GHD patient with baseline
low BMD and high fat mass who is already at high risk for
further metabolic complications. Therefore, we obtain a baseline dual energy x-ray absorptiometry scan of the lumbar
spine to quantify vBMD and fat mass. We assess lumbar
spine vBMD because most outcome studies provided data
using this measurement. We treat patients with the adult
dose (12.5 ␮g/kg䡠d) rather than the pediatric (40 –70 ␮g/
kg䡠d) or intermediate (25 ␮g/kg䡠d) dose, because the studies
that compared different doses did not detect significant differences in outcome. We also discuss with our patients the
possibility of “treatment holiday” because many patients are
weary of the administration of daily injections. There have
been no studies to date investigating the effects of short
treatment holidays on the metabolic status of transition patients. In theory, if baseline body composition and lumbar
vBMD are normal, then beginning GH therapy promptly if
these parameters deteriorate may not result in adverse outcomes. We recognize that despite our treatment recommendations, the final decision may be determined by the availability of reimbursement by third-party payers.
Nevertheless, continued regular follow-up of untreated patients is mandatory to monitor for any adverse changes in
body composition or BMD.
The effect of discontinuing GH in patients with partial
GHD has been the subject of one study. In this study, patients
J Clin Endocrinol Metab, April 2007, 92(4):1195–1200
1199
were diagnosed with partial GHD if retesting with ITT and
an alternate test (clonidine-betaxolol) resulted in GH peaks
less than 10.0 ␮g/liter on both tests using a monoclonal GH
assay. The patient population consisted primarily of iGHD
patients. The group with partial GHD had slightly but significantly higher fat mass and lower LBM indices than patients who were diagnosed as GH sufficient (32). Whether the
lack of GH has an effect on BMD in this population was not
determined. At this time, we do not treat patients with partial
GHD because there are few data on the effects of GH withdrawal or treatment in this population. However, considering the results of this study, we advocate clinical monitoring,
especially in at-risk populations.
Back to the Patient
Seven weeks after stopping GH treatment, J.D. underwent
GHRH-arginine testing. He had a peak GH level of 2.7 ␮g/
liter and a pretest IGF-I level of 96 ␮g/dl (182–780). A baseline dual energy x-ray absorptiometry of the lumbar spine
revealed a vBMD z-score of ⫺0.5 and percentage fat mass of
8.2%. He declined therapy and, 1 yr later, his BMD and fat
mass were unchanged. We scheduled follow-up in 1 yr with
an adult endocrinology colleague experienced in GH treatment of young adults.
Conclusions
Despite increasing knowledge about the effect of GH, there
is ongoing debate about nearly every aspect of GH therapy.
The use of GH in adolescents in the transition phase is in its
infancy and is likely to stimulate more debate. We advocate
additional research to determine 1) the evolution of tissue
maturation in the healthy vs. GHD populations, 2) the consequences of a short-term holiday from GH in the transition
population, and 3) the effect, if any, of GH in the transition
phase on morbidity from fractures and cardiovascular disease. Only long-term follow-up of patients using prospective
studies and data banks will answer these questions. Finally,
we recommend the establishment of specialized clinics such
as those for cystic fibrosis and diabetes mellitus to improve
compliance and follow-up during the transition to adult
services.
Acknowledgments
Received January 23, 2007. Accepted February 21, 2007.
Address all correspondence and requests for reprints to: Sally Radovick, M.D., Division of Pediatric Endocrinology, Department of Pediatrics, The Johns Hopkins University School of Medicine, 600 North Wolfe
Street,
CMSC
406,
Baltimore,
Maryland
21287.
E-mail:
[email protected].
Disclosure Statement: The authors have nothing to disclose.
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