Why Retest Young Adults with Childhood-Onset Growth Hormone Deficiency?
H. de Boer and
E. A. van der Veen
Address all correspondence and requests for reprints to: Dr. Hans de Boer, Spaarne Ziekenhuis Haarlem, P.O. Box 1644, 2003 BR Haarlem, The Netherlands.
 |
Introduction
|
---|
In the past decade it has become increasingly
clear that growth hormone deficiency (GHD) has clinical implications
for adult man. The main characteristics of the adult GHD syndrome are
an increased subcutaneous and visceral fat mass, a reduced
extracellular fluid volume, a subnormal muscle mass, a low bone
density, a reduced cardiac performance, moderately elevated serum low
density lipoprotein (LDL) cholesterol levels, reduced physical
performance, impaired cognitive function, and reduced well-being (1, 2). Many of these abnormalities are at least partially reversible with
GH replacement started in adult life. Based on these observations the
concept is emerging that it might be advisable not to stop GH
replacement therapy in GHD adolescents who have reached their final
height.
The main objective of the present review is to evaluate whether current
evidence is sufficiently strong to support a policy that proposes
continuation of GH treatment in young adults with a diagnosis of GHD in
childhood to prevent the development of the adult GHD syndrome in these
patients.
 |
The Consequences of Stopping GH Treatment
|
---|
The aim of continuation of GH replacement in adulthood is to
prevent GHD-related morbidity without introducing new risks associated
with the institution of GH treatment. Treatment strategies aimed at
prevention of GHD-related morbidity are indicated if the long-term
consequences of adult GHD are known to be severe and if the efficacy of
treatment has been firmly established. The consequences of prolonged GH
depletion in adults have been evaluated in patients with adult-onset
GHD (AO-GHD) as well as in adults with childhood-onset GHD (CO-GHD).
Although both patient groups show marked similarities, they are not
entirely comparable. Attanasio et al. (3) recently
demonstrated that adults with CO-GHD (n = 74) had lower serum
insulin-like growth factor I (IGF-I) levels, lower body height, more
severe decrease in lean body mass, less severe increase in total
cholesterol levels, higher HDL-cholesterol levels, and higher
osteocalcin levels, and that they scored better on quality-of-life
assessments than patients with AO-GHD. The logical consequence of these
observations is that an assessment of the severity of the consequences
of GHD for adults with CO-GHD will lose accuracy if the analysis
includes data obtained from patients with AO-GHD.
The main findings of controlled studies performed in adults with CO-GHD
are summarized in Table 1
(see references 411). They
provide cross-sectional data of patients with severe GHD who have been
without GH for a mean period of approximately 8 yr. The first
impression is that abnormalities of this degree should be avoided if
possible. However, it is uncertain whether the current generation of
GHD adolescents will develop abnormalities of a similar degree once
their GH treatment is discontinued. The observations on body
composition and on physical and psychological performance are not
exclusively the result of withdrawing GH treatment at final height, but
they also reflect the consequences of suboptimal GH treatment during
childhood and adolescence. According to current standards, most
patients who were included in these studies received suboptimal GH
treatment during childhood because of the limited supply of
pituitary-derived GH. The effects on final height were poor. Mean final
height was approximately 2 SD below the normal mean. It is
most likely that the treatment regimens during childhood were also
insufficient to normalize body composition and physical performance,
and that discontinuation of GH treatment at final height only caused a
further deterioration of preexisting abnormalities. The relative
impacts of suboptimal treatment during childhood and the
discontinuation of GH treatment in early adulthood are not known.
There are currently only two uncontrolled, longitudinal studies showing
that discontinuation of GH treatment does have deleterious effects on
body composition (12, 13). In a study of 8 patients (7 males, 1 female)
with a peak GH response less than 5 µg/L, Rutherford et
al. (12) showed that discontinuation of GH treatment for 1 yr was
associated with an increase in body fat from 19.5 \ 8.6% to
24.1 \ 9.5%, assessed by measurement of skinfold thickness.
Muscle mass and muscle strength decreased by approximately 5% during
this period. Colle et al. (13) studied 5 male adolescents
and found that body fat increased by 4.1 \ 2.2 kg in the three
months following discontinuation of GH treatment. This observation was
based on bioimpedance analysis, a method that tends to overestimate
changes in body fat in GHD patients (2). Controlled or uncontrolled
longitudinal studies demonstrating that discontinuation of GH
replacement has deleterious effects on cardiac muscle structure and
function or that it adversely affects the build-up and maintenance of
bone mass are currently not available. In a recent study on bone
density in 33 young adults with CO-GHD we found no significant change
in bone mineral density (BMD) during a mean follow-up of 2 yr (our
unpublished data). This is in agreement with the findings of Kaufman
et al. (6) who studied BMD in 19 GHD patients for a period
of 1015 months.
The current generation of GHD adolescents is expected to start adult
life in better condition because they have received more optimal
treatment during childhood. Nowadays, treatment is started at an
earlier age, and GH replacement doses are much higher than previously
employed. Both measures serve to improve final height. With these
higher doses of GH a normalization of bone density can be achieved
(14). It remains to be demonstrated whether the recent improvements of
GH treatment during childhood and adolescence will also lead to a
normalization of body fat, muscle mass, cardiac function, and physical
performance at final height.
In conclusion, although the existence of the adult GHD syndrome is
definitely established, it is conceivable that the clinical picture in
the coming generation of adults with CO-GHD may be somewhat different
and less severe than demonstrated in patients who received suboptimal
treatment during childhood and adolescence.
 |
Who Is at Risk to Develop the Adult GHD Syndrome?
|
---|
Identification of the risk factors that determine the likelihood
of developing the adult GHD syndrome is an essential step in the
process of selecting the patients that may or may not benefit from
continuation of GH treatment. Table 2
summarizes the
characteristics of adults with CO-GHD who were included in studies that
evaluated the consequences of GHD or the efficacy of GH treatment
(327). It is worth noting that 85100% of the patients had a peak
GH response less than 5 µg/L, and that the number of women who were
studied was extremely small. Thus, any conclusion or prediction made on
the basis of these studies is only valid for male patients with severe
GHD. So far, there are no data supporting the conclusion that patients
with partial GHD, i.e. those with a peak GH response of
510 µg/L, are at risk to develop the adult GHD syndrome, nor has it
been shown that the consequences of GHD are of similar severity in men
and in women.
View this table:
[in this window]
[in a new window]
|
Table 2. Characteristics of adults with childhood-onset GHD
in A) controlled and uncontrolled studies evaluating the consequences
of GHD, and in B) studies evaluating the effects of GH treatment
|
|
 |
The Efficacy of GH Treatment
|
---|
In adults with CO-GHD who have developed the adult GHD syndrome,
GH treatment reduces body fat (4, 24), increases muscle mass (5, 24)
and bone density (21, 23, 26), improves cardiac structure and function
(9), physical performance (24), and cognitive function (28), and may
lower serum LDL cholesterol (20). The latter only occurs in patients
initially presenting with an elevated LDL cholesterol level. As
observed previously, the effects of treatment have mainly been studied
in men who were severely GHD and who had discontinued previous GH
treatment for short stature for approximately 8 yr. The observed
GH-induced changes in body composition were large. Subcutaneous fat
mass decreased by 27% (95% CI: 2232%) and intraabdominal fat mass
by 47% (95% CI: 3657%) (4). Anthropometric measurements indicated
that muscle mass increased by 2025% after 1 yr of GH treatment (5).
In 6 patients studied for 30 months, lumbar spine bone mineral content
increased by 7% and forearm bone mineral content by 10% (23). After 3
yr of GH treatment the increase in exercise capacity was approximately
40% (24). The GH-induced decline in LDL cholesterol amounted to
approximately 10% (20). The overall conclusion is that the changes
induced by GH treatment are sufficiently large to consider this mode of
treatment beneficial and clinically relevant in CO-GHD men who have
developed the adult GHD syndrome. Moreover, results of long-term
treatment are encouraging because they indicate that improvements
achieved during short-term treatment are sustained (24). Whether
treatment will be equally effective in women with CO-GHD remains to be
demonstrated. In AO-GHD adults there is some evidence emerging that
women are less responsive to GH treatment than men (29, 30, 31).
 |
Why Retest the GH-Axis in Young Adults with CO-GHD?
|
---|
Obviously, the objective of retesting CO-GHD adults is to confirm
the diagnosis of GHD once they have reached adulthood to identify the
patients who may be at risk of developing the adult GHD syndrome. One
of the main reasons to strongly advocate retesting is that a former
diagnosis of GHD in childhood is insufficient evidence to conclude that
a patient will be GHD for life.
Cacciari et al. (32) clearly demonstrated this when they
retested a large group of children with isolated GHD (IGHD) 4 weeks
after interruption of GH replacement therapy. In their first study 13
out of 53 children (24.5%) had a normalization of GH peak responses to
2 provocative tests. In a subsequent, more extensive study, 44 out of
132 children (28.9%) had a normalization of the GH response (33).
Normalization of GH responsiveness is also frequently observed if
retesting is performed in adulthood. Longobardi et al. (34)
retested 69 adults with childhood-onset GHD of varying etiology using a
combination of GHRH plus pyridostigmine (GHRH PD). Thirty
patients (43%) had a normal GH response, defined as peak GH response
greater than 10 µg/L. A subsequent insulin tolerance test (ITT)
revealed that 3 patients with a normal response to GHRH PD had a
subnormal response to ITT, whereas all patients who had a subnormal
response to GHRH PD also had a subnormal response to ITT. Thus,
if the ITT is used as the gold standard, 27 out of 69 (40%) patients
had a normalization of GH responsiveness. This is in close agreement
with findings in other studies. Table 3
summarizes the
prevalence of normalization of GH responsiveness in CO-GHD adults,
observed in studies using either the ITT or the arginine stimulation
test (AST) (12, 35, 36, 37). The patients are categorized according to the
etiology of GHD. Normalization of GH secretion was observed in 35% of
the patients with IGHD. As expected, it was rare in patients with
extensive damage in the hypothalamic-pituitary area. It occurred in
11% of the patients with multiple pituitary hormone deficiencies
(MPHD), in 3% of the patients with irradiation-induced GHD, and in
none of the patients who had been treated for craniopharyngioma. The
chance of a normal GH response upon retesting in adulthood is much
higher in patients with a previous diagnosis of partial GHD (GH peak
response 510 µg/L) than in those with complete GHD (GH peak
response <5 µg/L). In a study of 131 patients with a diagnosis of
GHD in childhood, normalization of GH responsiveness was observed in
36% of the patients with a previous diagnosis of complete GHD and in
as much as 71% of the patients with previously established partial GHD
(38). The likelihood of normalization of GH responsiveness is not
different for men and women, and it is independent of whether the
previous diagnosis of GHD was established before or during puberty
(38).
View this table:
[in this window]
[in a new window]
|
Table 3. Normalization of GH responsiveness in CO-GHD
patients upon retesting in adulthood: summary of studies using the
insulin tolerance test or the arginine stimulation test
|
|
Another reason to advocate retesting is that the biochemical criteria
for a diagnosis of GHD in adults are different from those used to
accept the diagnosis of GHD in children. Although a consensus on the
diagnosis of GHD in adulthood has not yet been reached, most will agree
that a GH peak response less than 5 µg/L is diagnostic (39). This
cut-off limit, also represents the upper limit of the GH responses
observed in the majority of patients who have acquired the
abnormalities characteristic of the adult GHD syndrome (Tables 1
and 2
). The practical consequence of using the 5 µg/L limit is that only
a proportion of the adolescents who are now receiving GH treatment for
short stature will be eligible for continuation of GH treatment in
adulthood. Nicolson et al. (37) evaluated the prevalence of
severe GHD in adults who received GH replacement in childhood. Using
the insulin or arginine test for reevaluation of GH secretion in
adulthood, they found that 53 of 88 patients (60%) had a peak GH
response less than 4.5 µg/L (25). In Taubers study (38), only 30
out of 131 patients (23%) had a peak GH response less than 5 µg/L
after retesting with clonidine betazolol. If we combine these
data, approximately 60% of the children with a former diagnosis of GHD
will not be eligible for continuation of GH treatment in adulthood if a
cut-off limit of 5 µg/L is used.
 |
The Preferred Pharmacological GH Stimulation Test in Adulthood
|
---|
In the past 30 yr a large number of physiological and
pharmacological GH stimulation tests have been developed to evaluate
the integrity of the GH-axis. In children, the most frequently used
pharmacological stimuli are insulin, arginine, levo-dopa, clonidine,
and glucagon (40). In adults the GHRH test is also frequently employed
(2, 34). The limitations of each test are well known (2, 40). The
recent statement that "it is simplistic and unrealistic to believe
that a single biochemical assay can be relied upon to establish a
diagnosis of GHD" (41) deserves a prominent place in the office of
clinicians involved with GH treatment. However, until a more
appropriate diagnostic protocol has been developed and validated, we
have to live with the limitations of the conventional methodology for
establishing a diagnosis of GHD. For research purposes as well as for
clinical decision making it would be better if the number of
provocative tests used at various centers were reduced to a minimum and
if the biochemical approach to diagnose GHD was thoroughly standardized
worldwide. A comparison of study results is only possible if selection
and categorization of patients is based on a similar test procedure. We
strongly advocate inclusion of the ITT in all diagnostic procedures
that aim to establish a diagnosis of GHD in adults. In some pediatric
centers the ITT has fallen from favor because of the chance of adverse
effects resulting from hypoglycemia or overly vigorous correction of
hypoglycemia (42). In adults, however, this test appears to be a safe
procedure when performed in an experienced endocrine unit with adequate
supervision. Hoffman (43) summarized the ITT experience of 3 centers
and found that, in 1 out of 443 tests (0.2%), an adverse event had
occurred. This one patient had a hypoglycemia-induced seizure and
recovered without sequelae. The ITT has a high diagnostic accuracy in
adults (39), and it induces a more profound GH release than arginine,
glucagon, clonidine, levo-dopa, or exercise (44, 45, 46). A final argument
to favor the ITT is that it is one of the most frequently used tests in
studies that have evaluated the consequences of GHD in adults. It is
debatable which test should be used if the ITT is contraindicated.
There are several options, such as the glucagon, the arginine, the
levo-dopa, or the GHRH test, but the number of comparative studies is
too small to give firm recommendations as to which test is the best
alternative for the ITT. The use of the clonidine test is not
recommended. In healthy adults it induced peak GH responses that were
indistinguishable from placebo (44).
Serum IGF-I and IGFBP-3 measurements are commonly used as additional
instruments to evaluate the GH status in childhood. In adults with
childhood-onset GHD, the diagnostic value of serum IGF-I and IGFBP-3
measurements is comparable with that in GHD children (3, 47, 48). In
patients with adult-onset pituitary disease these markers have limited
diagnostic accuracy. Normal levels were found in a large proportion of
patients who had a subnormal GH response to ITT (43). A satisfactory
explanation for this somewhat surprising observation is lacking.
 |
Conclusions and Recommendations
|
---|
We strongly advocate retesting of all patients with CO-GHD,
preferably by ITT, once they have reached their final height. Retesting
serves to identify the patients who have so called transient GHD and
who are therefore not at risk to develop the adult GHD syndrome.
Patients with a GH response less than 5 µg/L are most likely to
develop the adult GHD syndrome if GH treatment is stopped at final
height, and this group is expected to benefit substantially from GH
treatment in adulthood. The prognosis of patients with a GH response of
510 µg/L is not known.
The efficacy of a treatment strategy that aims to prevent the
development of the adult GHD syndrome in patients with CO-GHD remains
to be demonstrated in placebo-controlled trials. As long as these data
are not available it is recommended that all patients with a reduced
GH-response be monitored for a period of at least 5 yr, with special
emphasis on body composition, serum lipid levels, and physical
performance. Parameters that reliably predict how severe the
abnormalities will be in due time if GH treatment is stopped, or that
reliably predict what the exact benefits are of continuation of GH
treatment for an individual patient have not been identified yet. For
the present, therefore, it seems most plausible to base the decision of
GH treatment in adulthood on developments observed in the patient after
discontinuation of GH treatment for short stature. In view of our still
limited knowledge it presently appears to be the only reliable approach
to demonstrate that a patient may or may not need GH treatment in adult
life. An exception should be made for those GHD patients with a low
bone mineral density at final height. Continuation of GH treatment is
advised until normalization of bone mineral density is achieved.
Received April 9, 1997.
Accepted April 16, 1997.
 |
References
|
---|
-
Cuneo RC, Salomon F, McGauley GA, Sönksen
PH. 1992 The growth hormone deficiency syndrome in adults. Clin
Endocrinol. 37:387397.[Medline]
-
De Boer H, Blok GJ, van der Veen EA. 1995 Clinical
aspects of growth hormone deficiency in adults. Endocr Rev. 16:6386.[Medline]
-
Attanasio AF, Lamberts SWJ, Matranga AMC, et al. 1997 Adult growth hormone (GH)-deficient patients demonstrate
heterogeneity between childhood onset and adult onset before and during
human GH treatment. J Clin Endocrinol Metab. 82:8288.[Abstract/Free Full Text]
-
De Boer H, Blok GJ, Voerman B, Derriks P, van der Veen
EA. 1996 Changes in subcutaneous and visceral fat mass during
growth hormone replacement therapy in adult men. Int J Obes. 20:580587.
-
De Boer H, Blok GJ, Voerman B, de Vries P,
Popp-Snijders C, van der Veen EA. 1996 The optimal growth hormone
replacement dose in adults, derived from bioimpedance analysis. J
Clin Endocrinol Metab. 80:20692076.[Abstract]
-
Kaufman JM, Taelman P, Vermeulen A, Vandeweghe M. 1992 Bone mineral status in growth hormone deficient males with
isolated and multiple pituitary deficiencies of childhood onset. J
Clin Endocrinol Metab. 74:118123.[Abstract]
-
De Boer H, Blok GJ, van Lingen A, Teule GJJ, Lips P,
van der Veen EA. 1994 Consequences of childhood-onset growth
hormone deficiency for adult bone mass. J Bone Miner Res9
:13191326.
-
Merola B, Cittadini A, Colao A, et al. 1993 Cardiac structural and functional abnormalities in adult patients with
growth hormone deficiency. J Clin Endocrinol Metab. 77:16581661.[Abstract]
-
Amato G, Carella C, Fazio S, et al. 1993 Body
composition, bone metabolism, and heart structure and function before
and after GH replacement therapy at low doses. J Clin Endocrinol
Metab. 77:16711676.[Abstract]
-
De Boer H, Blok GJ, Voerman HJ, Phillips M, Schouten
JA. 1994 Serum lipid levels in growth hormone deficient men.
Metabolism 43:199203.
-
Deijen JB, de Boer H, Blok GJ, van der Veen EA. 1996 Cognitive impairments and mood disturbances in growth hormone
deficient men. Psychoneuroendocrinology. 21:313322.[CrossRef][Medline]
-
Rutherford OM, Jones DA, Round JM, Buchanan CR, Preece
MA. 1991 Changes in skeletal muscle and body composition after
discontinuation of growth hormone treatment in growth hormone deficient
young adults. Clin Endocrinol. 34:469475.[Medline]
-
Colle M, Auzerie J. 1993 Discontinuation of growth
hormone therapy in growth hormone deficient patients: assessment of
body fat mass using bioelectrical impedance. Horm Res. 39:192196.[Medline]
-
Saggese G, Baroncelli GI, Bertelloni S, Barsanti S. 1996 The effect of long-term growth hormone (GH) treatment on bone
mineral density in children with GH deficiency. Role of GH in the
attainment of peak bone mass. J Clin Endocrinol Metab. 81:30773083.[Abstract]
-
Binnerts A, Deurenberg P, Swart R, Wilson JH, Lamberts
SWJ. 1992 Body composition in growth hormone deficient adults. Am J Clin Nutr. 55:918923.[Abstract]
-
De Boer H, Blok GJ, Voerman HJ, de Vries P, van der Veen
EA. 1992 Body composition in adult growth hormone deficient men,
assessed by anthropometry and bioimpedance analysis. J Clin
Endocrinol Metab. 75:833837.[Abstract]
-
Hyer SL, Rodin DA, Tobias JH, Leiper A, Nussey SS. 1992 Growth hormone deficiency during puberty reduces adult bone
mineral density. Arch Dis Child 57:14721474.
-
Sartorio A, Conti A, Monzani M. 1993 New markers of
bone and collagen turnover in children and adults with growth hormone
deficiency. Postgrad Med J. 69:846850.[Abstract]
-
Jorgensen JOL, Pedarsen SA, Thuesen L, et al. 1989 Beneficial effects of growth hormone treatment in GH-deficient adults.
Lancet. I:12211224.
-
Binnerts A, Swart GR, Wilson JHP, et al. 1992 The
effect of growth hormone administration in growth hormone deficient
adults on bone, protein, carbohydrate and lipid homeostasis, as well as
on body composition. Clin Endocrinol. 37:7987.[Medline]
-
OHalloran DJ, Tsatsoulis A, Whitehous RW, Holmes SJ,
Adams JE, Shalet SM. 1993 Increased bone density after recombinant
human growth hormone (GH) therapy in adults with isolated GH
deficiency. J Clin Endocrinol Metab. 76:13441348.[Abstract]
-
Sartorio A, Conti A, Monzani M, Morabito F, Faglia
G. 1993 Growth hormone treatment in adults with GH deficiency:
effects on new biochemical markers of bone and collagen turnover. J
Endocrinol Invest. 16:893898.[Medline]
-
Vandeweghe M, Taelman P, Kaufman JM. 1993 Short-
and long-term effects of growth hormone treatment on bone turnover and
bone mineral content in adult growth hormone deficient males. Clin
Endocrinol. 39:409415.[Medline]
-
Jorgensen JOL, Thuesen L, Müller J, Ovesen P,
Skakkebaek NE, Christiansen JS. 1994 Three years of growth hormone
treatment in growth hormone deficient adults: near normalization of
body composition and physical performance. Eur J Endocrinol130
:224228.
-
Balducci R, Toscano V, Pasquino AM, et al. 1995 Bone turnover and bone mineral density in young adult patients with
panhypopituitarism before and after long-term growth hormone therapy.
Eur J Endocrinol 132:4246.
-
Amato G, Izzo G, la Montagna G, Bellastella A. 1996 Low-dose recombinant human growth hormone normalizes bone metabolism
and cortical bonde density and improves trabecular bone density in
growth hormone deficient adults without causing adverse effects. Clin
Endocrinol. 45:2732.[Medline]
-
De Boer H, Blok GJ, Popp-Snijders C, Stuurman L, Baxter
RC, van der Veen EA. 1996 Monitoring of growth hormone replacement
therapy in adults, based on measurement of serum markers. J Clin
Endocrinol Metab. 81:13711377.[Abstract]
-
Deijen JB, de Boer H, van der Veen EA. In press.
Cognitive changes during GH replacement in adult men.
Psychoneuroendocrinology.
-
Johannsson G, Bjarnason R, Brammert M, et al. 1996 The individual responsiveness to growth hormone (GH) treatment in
GH-deficient adults is dependent on the level of GH-binding protein,
body mass index, age and gender. J Clin Endocrinol Metab. 81:15751581.[Abstract]
-
Johannsson G, Rosen T, Bosaeus I, Sjöström
L, Bengtsson BA. 1996 Two years of growth hormone (GH) treatment
increases bone mineral content and density in hypopituitary patients
with adult-onset GH deficiency. J Clin Endocrinol Metab. 81:28652873.[Abstract]
-
Burman P, Johansson AG, Siegbahn A, Vessby B, Karlsson
FA. 1997 Growth hormone (GH)-deficient men are more responsive to
GH replacement therapy than women. J Clin Endocrinol Metab. 82:550555.[Abstract/Free Full Text]
-
Cacciari E, Tassoni P, Parisi G, et al. 1992 Pitfalls in diagnosing impaired growth hormone (GH) secretion:
Retesting after replacement therapy of 63 patients defined as GH
deficient. J Clin Endocrinol Metab. 74:12841289.[Abstract]
-
Cacciari E, Tassoni P, Cicognani A, et al. 1994 Value and limits of pharmacological and physiological tests to diagnose
growth hormone (GH) deficiency and predict therapy response: first and
second retesting during replacement therapy of patients defined as GH
deficient. J Clin Endocrinol Metab. 79:16631669.[Abstract]
-
Longobardi S, Merola B, Pivonello R, et al. 1996 Reevaluation of growth hormone (GH) secretion in 69 adults diagnosed as
GH-deficient patients during childhood. J Clin Endocrinol Metab. 81:12441247.[Abstract]
-
Clayton PE, Price DA, Sjalet SM. 1987 Growth
hormone state after completion of treatment with growth hormone. Arch
Dis Child. 62:222226.[Abstract]
-
Wacharasindhu S, Cotterill AM, Camacho-Hübner C,
Besser GM, Savage MO. 1996 Normal growth hormone secretion in
growth hormone insufficient children retested after completion of
linear growth. Clin Endocrinol. 45:553556.[Medline]
-
Nicolson A, Toogood A, Rahim A, Shalet SM. 1996 The
prevalence of severe growth hormone deficiency in adults who received
growth hormone replacement in childhood. Clin Endocrinol. 44:311316.[Medline]
-
Tauber M, Moulin P, Pienkowski C, Jouret B, Rochiccioli
P. 1997 Growth hormone (GH) retesting and auxological data in 131
GH-deficient patients after completion of treatment. J Clin
Endocrinol Metab. 82:352356.[Abstract/Free Full Text]
-
Hoffman DM, OSullivan AJ, Baxter RC, Ho KKY. 1994 Diagnosis of growth hormone deficiency in adults. Lancet343
:10641068.
-
Rosenfeld RG, Albertsson-Wikland K, Cassorla F, et
al. 1995 Diagnostic controversy: the diagnosis of childhood growth
hormone deficiency revisited. J Clin Endocrinol Metab. 80:15321540.[Medline]
-
Rosenfeld RG. 1997 Is growth hormone deficiency a
viable diagnosis? J Clin Endocrinol Metab. 82:349351.[Free Full Text]
-
Shah A, Stanhope R, Mathew D. 1992 Hazards of
pharmacological tests or growth hormone secretion in childhood. Br
Med J 304:316317.
-
Hoffman DM, Ho KKY. Diagnosis of GH deficiency in
adults. In: Growth hormone in adults, A. Juul and JOL. Jorgensen,
Cambridge University Press, 1996, page 168185.
-
Rahim A, Toogood AA, Shalet SM. 1996 The assessment
of growth hormone status in normal young adult males using a variety of
provocative agents. Clin Endocrinol 45:557562.
-
Lin T, Tucci JR. 1974 Provocative tests of growth
hormone release. Ann Int Med. 80:464469.[Medline]
-
Cain JP, Williams GH, Dluhy RG. 1972 Glucagon-initiated human growth hormone release: a comparative study. Can Med Assoc J. 107:617622.[Medline]
-
De Boer H, Blok GJ, Popp-Snijders C, van der Veen
EA. 1994 Diagnosis of growth hormone deficiency in adults. Lancet343
:16451646. (Letter).
-
Janssen YJH, Frölich M, Roelfsema F. 1997 A
low starting dose of genotropin in growth hormone deficient adults. J Clin Endocrinol Metab. 82:129135.[Abstract/Free Full Text]