Is Growth Hormone Deficiency a Viable Diagnosis?
Ron G. Rosenfeld and
M. D.
Doernbecher Childrens Hospital
Oregon Health Sciences University
Portland, Oregon 97201
Address correspondence and requests for reprints to: Ron G. Rosenfeld, MD, Department of Pediatrics, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201.
 |
Introduction
|
---|
One of the primary responsibilities of the
pediatric endocrinologist is the identification of children with
endocrine causes of growth failure (1). Whether retardation of growth
is the result of hypothyroidism, glucocorticoid excess, inborn errors
of metabolism, or pituitary abnormalities, prompt diagnosis may allow
early initiation of corrective therapy and, ideally, a period of
"catch-up" growth and normalization of stature before epiphyseal
fusion occurs.
Although statistics vary widely, the best estimates place the incidence
of idiopathic growth-hormone deficiency (GHD) at approximately 1:4000
(2); to these cases one must add the various causes of acquired GHD.
This diagnosis of GHD thus encompasses a wide spectrum of clinical
conditions, including structural defects of the hypothalamus or
pituitary, abnormal synthesis or secretion of hypothalamic factors,
deletions or mutations of the Pit-1 gene, abnormalities of the receptor
for GHRH, hereditary forms of isolated GHD, and acquired defects of GH
synthesis or secretion, such as tumors involving the hypothalamus or
pituitary (1). While congenital GHD may be associated with stigmata
such as hypoglycemia, microphallus, cryptorchidism, nystagmus, or
blindness, the basis of the clinical diagnosis of GHD remains
auxological. Short stature, accompanied by growth deceleration, is the
most important clinical evidence in support of a diagnosis of GHD. Many
of the problems associated with the diagnosis of GHD are the result of
inappropriate testing of children who do not have genuine growth
failure or other signs of GHD. While the absolute clinical criteria for
considering a diagnosis of GHD may be somewhat arbitrary, this author
suggests the following as guidelines:
- severe growth retardation (height >3 standard deviations
(SD) below the mean for age in the absence of an
alternative explanation;
- moderate growth retardation (height -2 to -3 SD
below the mean for age plus growth deceleration (height velocity <25th
percentile for age) in the absence of an alternative
explanation;
- severe growth deceleration (height velocity <5th percentile
for age) in the absence of an alternative explanation;
- a predisposing condition (e.g. cranial irradiation)
plus growth deceleration;
- other evidence of pituitary dysfunction (e.g.
other pituitary deficiencies, neonatal hypoglycemia, microphallus)
Even in the appropriate clinical setting, however, the diagnosis
of GHD remains problematic, largely because measurement of
physiological GH secretion is fraught with difficulties (3). In part,
this is because of the pulsatile nature of GH secretion, with peaks
typically occurring during slow-wave electroencephalographic rhythms in
phases 3 and 4 of sleep. This pulsatility reflects the interplay of a
wide variety of neurotransmitters, hypothalamic peptides, and hormones,
including, to name a few, GHRH, somatostatin,
bombesin/gastrin-releasing peptide, galanin, opiate-like peptides, and
sex steroids. Another variable, which has received little attention, is
that GH secretion must be assessed in the face of negative feedback by
the insulin-like growth factors (IGFs), much as TSH and ACTH
concentrations should be interpreted in light of concomitant serum
thyroid hormone and cortisol, respectively. A given level of GH
secretion in the face of low serum IGF concentrations may, for example,
be pathological, relative to similar GH concentrations in the face of
normal IGF concentrations.
The pulsatile nature of GH secretion renders assessment of random serum
GH concentrations virtually worthless in the diagnosis of GHD. Instead,
the convention for over 30 yr has been to measure serum GH following
pharmacological stimulation of the pituitary, an assessment,
presumably, of pituitary GH "reserve" or "secretory capability"
(4). While such provocative testing is of value, particularly in the
identification of patients with complete or severe GHD, total reliance
on these tests has proven to be problematic for a variety of reasons
(3).
- Provocative testing is, by its very nature,
nonphysiological. Whether such tests employ insulin-induced
hypoglycemia, arginine, L-DOPA, clonidine, glucagon, or other
secretagogues, such tests clearly do not replicate normal secretory
dynamics.
- No satisfactory mechanism has been developed for resolving
conflicting data from two or more tests; the commonly employed paradigm
of requiring failure on two provocative tests does not address the
simple question of two out of how many?
- The definition of what constitutes an abnormal response to
provocative testing is arbitrary. The availability of recombinant
DNA-derived human GH in the mid-1980s resulted in a loosening of the
diagnostic cut-off from 57 ng/mL to 10 ng/mL, on the basis of no
physiological data.
- The age-dependency and sex steroid-dependency of GH secretory
dynamics have not been established adequately. The studies of Marin
et al. (5) have shown, for example, that in the absence of
sex steroid priming, the lower normal limit for peak GH in prepubertal
children is as low as 1.9 ng/mL. Indeed, in that study, 61% of
normal-stature prepubertal children failed to raise their serum GH
concentrations above 7 ng/mL following provocative stimulation and
would, thereby, have met conventional criteria for a diagnosis of
GHD.
- The reproducibility of provocative GH testing has never been
demonstrated convincingly.
- The impact of adiposity on responsiveness to GH
provocative testing has not been addressed adequately.
- The potential effect of psychiatric disturbances such as
depression on GH provocative testing has not been assessed properly,
even though data exist demonstrating that depression and similar
clinical situations can impact GH secretion (6).
- Interassay variations in GH radioimmunoassays can be as great
as 2- to 3-fold among major reference laboratories, presumably
reflecting variability in molecular forms of GH among patients, use of
polyclonal vs. monoclonal antibodies, and employment of
different diluents and standards.
- Provocative GH testing is associated with significant cost,
discomfort to the patient, and some element of risk. Deaths have
occurred during both insulin and arginine stimulation tests.
- Demonstration of normal provocative testing does not exclude
the possibility of various forms of GH insensitivity (GHI) (7).
The paper by Tauber et al. (8) in the current issue of
The Journal of Clinical Endocrinology and Metabolism (see
page 352) emphasizes a number of important limitations of conventional
methodologies for establishment of a diagnosis of GHD. Their findings
have relevance not only for the diagnosis of GHD in children, but also
have importance for adults with GHD, a group of patients that is
receiving considerable attention as potential candidates for GH
treatment. One hundred thirty-one patients identified as GHD as
children on the basis of provocative GH testing were retested during
late adolescence or adulthood, after cessation of GH treatment. Upon
re-evaluation, 67% of patients with "idiopathic" GHD diagnosed in
childhood had normalized their GH secretion. This was particularly true
for patients who initially had peak GH concentrations between 510
ng/mL, although even when the initial peak GH concentration was less
than 5 ng/mL, 36% of patients diagnosed with idiopathic GHD as
children normalized their provocative GH tests as adults. Although the
study is limited by a number of methodological issues, such as whether
sex steroid priming was performed in prepubertal patients and whether
the same GH radioimmunoassay and assay standards were employed
throughout the course of the study, the conclusions concerning the
fallibility of provocative GH testing are indisputable.
These serious limitations of the conventional methodology for
establishing a diagnosis of GHD have led to the proposal that a more
useful diagnostic paradigm would be the diagnosis of IGF deficiency (1, 9) The potential advantages of such an approach are readily evident: 1)
it is clear that the IGFs are the major hormones responsible for both
intrauterine and postpartum growth (10); 2) serum concentrations of the
critical GH-dependent peptides, IGF-1, IGFBP-3, and the acid-labile
subunit (ALS) have little, if any, diurnal variation and can be readily
assessed on a single, random blood sample (3, 9); 3) radioimmunoassays
for IGFBP-3 can be readily performed on unextracted serum samples and
are highly reproducible; 4) normal serum concentrations of IGFBP-3 are
in the µg/mL range, and assay sensitivity is not an issue; and 5)
documentation of IGF deficiency can then lead to a logical differential
diagnosis (Table 1
), which, in turn, lends itself to a
rational clinical and biochemical evaluation.
The potential value of a diagnosis of IGF deficiency, as well as the
practical utility of the various IGF-related assays, should not be
interpreted to mean that there is no clinical value of measurements of
GH secretion. Such measures, whether of spontaneous or stimulated GH
secretion, are critical to the characterization of
hypothalamic-pituitary function and have important practical value in
identification of patients who require further evaluation for potential
intracranial tumors or structural defects of the central nervous
system. Additionally, assessment of pituitary function may be of
importance in the diagnosis of hereditary disorders of GH synthesis or
secretion. On the other hand, an increasing number of studies, such as
those of Tauber and colleagues (8) have demonstrated that measurement
of GH secretion in children by provocative GH testing is fraught with
methodological and interpretative pitfalls and should not be the sole
factor employed in the diagnosis of GHD or IGF deficiency in children.
In reality, it is simplistic and, ultimately, unrealistic to believe
that a single biochemical assay can be relied upon to establish this
kind of clinical diagnosis. Complete biochemical assessment of a
patient with hypothyroidism requires measures of both thyroid and
pituitary function; similarly, a diagnosis of adrenal insufficiency
calls for assessment of both cortisol and ACTH secretion. We should
expect no less for the endocrine evaluation of a biological function as
complex as growth. The thorough assessment of growth failure should
require careful auxological evaluation, supplemented by appropriate
assessment of the GH-IGF axis and, ultimately, a reasoned
interpretation of the collective clinical, auxological, and biochemical
data.
 |
References
|
---|
-
Rosenfeld RG. 1996 Disorders of growth
hormone/IGF secretion and action. In: Sperling MA, ed. Pediatric
endocrinology. 3rd ed. Philadelphia; WB Saunders; 117169.
-
Lindsay R, Feldkamp M, Harris D, Robertson J, Rallison
M. 1994 Utah Growth Study: Growth standards and the prevalence of
growth hormone deficiency. J Pediatr. 125:2935.[Medline]
-
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]
-
Frasier SD. 1974 A review of growth hormone
stimulation tests in children. Pediatrics. 53:929937.[Abstract]
-
Marin G, Domene HM, Barnes KM, Blackwell BJ, Cassorla
FG, Cutler Jr GB. 1994 The effects of estrogen priming and puberty
on the growth hormone response to standardized treadmill exercise and
arginine-insulin in normal girls and boys. 79:537541.
-
Puig-Antich J, Novacenko H, Davies M, et al. 1984 Growth hormone secretion in prepubertal children with major depression.
I. Final report on response to insulin-induced hypoglycemia during a
depressive episode. Arch Gen Psychiatry, 41:455460.
-
Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre
J. 1994 Growth hormone (GH) insensitivity due to GH receptor
deficiency. Endocr Rev. 15:369390.[Abstract]
-
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]
-
Rosenfeld RG. 1996 Biochemical diagnostic
strategies in the evaluation of short stature: The diagnosis of
insulin-like growth factor deficiency. Horm Res. 46:170173.[Medline]
-
Woods KA, Camacho-Hubner C, Savage MO, Clark AJI. 1996 Intrauterine growth retardation and postnatal growth failure
associated with deletion of the insulin-like growth factor-I gene. N Engl J Med. 335:13631367.[Free Full Text]