0021-972X/98/$03.00/0 Vol. 83, No.

5
Journal of Clinical Endocrinology and Metabolism Printed in U.S.A.
Copyright © 1998 by The Endocrine Society

Comparison between Insulin-Induced Hypoglycemia and

Growth Hormone (GH)-Releasing Hormone 1 Arginine
as Provocative Tests for the Diagnosis of GH Deficiency
in Adults*
G. AIMARETTI, G. CORNELI, P. RAZZORE, S. BELLONE, C. BAFFONI, E. ARVAT,
F. CAMANNI, AND E. GHIGO
Division of Endocrinology, Department of Internal Medicine, University of Turin, 10126 Turin Italy

ABSTRACT positively (though weakly) associated with insulin-like growth fac-

There is now wide consensus that, within an appropriate clinical
context, GH deficiency (GHD) in adults must be shown biochemically
by provocative testing of GH secretion and that appropriate cut-off
limits have to be defined for each provocative test. Insulin-induced
hypoglycemia (ITT) is indicated as the test of choice, and severe GHD,
to be treated with recombinant human GH replacement, is defined by
a GH peak response to ITT of less than 3 mg/L. GHRH 1 arginine
(GHRH1ARG) is one of the most promising tests in alternative to ITT.
In fact, it has been reported as a potent, reproducible, and age-inde-
pendent test and that it is able to distinguish between GHD and
normal adults. The aim of the present study was to compare the GH
response to ITT and GHRH1ARG in a large group of hypopituitary
adults (n 5 40; 29 male and 11 female; age: 36.4 6 2.1 yr). The third
centile limit of the peak GH response to ITT has been reported as 5
mg/L, whereas in our lab, that to GHRH1ARG is 16.5 mg/L. In hy-
popituitary adults, the mean peak GH response to ITT (1.5 6 0.2 mg/L,
range: 0.1– 8.5 mg/L) was lower (P , 0.001) than that to GHRH1ARG
(3.0 6 0.4 mg/L, range 0.1–12.0 mg/L), though there was positive
correlation (r 5 0.61, P , 0.001) between the GH responses to the 2
tests. The peak GH response to GHRH1ARG, but not that to ITT, was
tor-I levels (r 5 0.35, P , 0.03). Childhood and adult onset GHD
patients, as well as patients with single and multiple pituitary in-
sufficiencies, had similar peak GH responses to ITT or GHRH1ARG.
Analyzing individual GH responses, 4/40 (10%) of the hypopituitary
patients had GH peaks higher than 5 mg/L after ITT; moreover, 3
other patients (7%) had GH peaks, after ITT, higher than 3 mg/L. On
the other hand, after GHRH1ARG, all patients had GH peaks lower
than 16.5 mg/L, whereas 21/40 (52.5%) had GH peaks higher than 3
mg/L. Because 3 mg/L is the arbitrary cut-off for ITT, the third centile
limit of which is 5 mg/L, we arbitrarily considered 9 mg/L as the cut-off
point for GHRH1ARG. It is noteworthy that 37/40 (92.5%) patients
had a GH peak,. after GHRH1ARG, below this limit. In conclusion,
our present results confirm that the ITT test is a reliable provocative
test for the diagnosis of adult GHD, whereas they show that the
GHRH1ARG test is, at least, as sensitive as the ITT test (provided
that appropriate cut-off limits are considered). Note that even the
arbitrary cut-off point below which severe GHD is demonstrated has
to be appropriate to the potency of the test. (J Clin Endocrinol Metab
83: 1615–1618, 1998)

I T HAS BEEN clearly demonstrated that adults with GH

deficiency (GHD) have impaired health, which improves
with GH replacement. In fact, GHD in adulthood leads to
clinical context, GHD in adults must be shown biochemi-
cally, by single provocative testing, provided that a repro-
ducible test with clear normative limits is available (9 –12).
impairment in body composition and structure functions This statement is based on evidence that the assays of insulin-
(such as increased abdominal fat mass, reduced lean body like growth factor-I (IGF-I) and IGF binding protein-3 per se
mass, lowered exercise capacity, impaired cardiac function, do not establish the diagnosis of adult GHD. In fact, normal
reduced bone mineral content), as well as to deranged li- IGF-I and/or IGF binding protein-3 levels do not exclude
poprotein and carbohydrate metabolism (1– 6). Moreover, GHD. This is caused by significant overlap between normal
shortened life expectancy, caused by increased cardiovascu- and GHD subjects for these parameters (9, 10, 13). Also, the
lar morbidity, has been recorded in hypopituitaric patients evaluation of spontaneous GH secretion over 24 h has no
with GHD (7, 8). Many authors (1–7) have showed the ben-
diagnostic value in adulthood (9). In fact, it is clearly reduced
eficial effects of replacement therapy on metabolism and
in GHD, but there is a clear overlap between normal and
body composition; and now, many countries have already
GHD subjects (even when ultrasensitive GH assays are used)
approved the use of recombinant human growth hormone
(rhGH) in adults with severe GHD. (14).
There is now wide consensus that, within an appropriate At present, the diagnosis of adult GHD is established only
by provocative testing of GH secretion, and insulin-induced
Received November 5, 1997. Revision received January 8, 1998. Re- hypoglycemia (ITT) is indicated as the test of choice (1, 9,
revision received February 3, 1998. Accepted February 10, 1998. 11–13, 15). The lowest limit of GH response to ITT in normal
Address all correspondence and requests for reprints to: E. Ghigo, subjects has been reported as 5 mg/L by some (but not by
M.D., Divisione di Endocrinologia, Ospedale Molinette, C.so Dogliotti
14, 10126 Torino, Italy
other) authors (1, 9, 15–17). Severe GHD to be treated with
* This work was supported by Ministero Universitá Ricerca Sci- rhGH replacement is defined by a GH peak to ITT lower than
entifica Tecnologica and Fondazione Studio Malattie Endocrino the arbitrary cut-off of 3 mg/L (11, 12). Contraindication to
Metaboliche.

1615

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1616 AIMARETTI ET AL. JCE & M • 1998
Vol 83 • No 5

ITT are ischemic heart disease, seizure disorders, and aging 8.8 –10.8% and 5.0 –9.5%, respectively, at IGF-I levels of 79.6 –766.4 and
(12). 79.4 –712.5 mg/L, respectively. Age-adjusted 3rd centile limits of nor-
mality for IGF-I levels in our laboratory (data derived from 336 normal
Alternative provocative tests of GH secretion have been subjects from 20 – 80 yr old) are: 108.5 mg/L between 20 –30 yr, 129.8
proposed and have to be used with appropriate cut-off limits mg/L between 31– 40 yr, 72.3 mg/L between 41–50 yr, 62.4 mg/L between
(10, 12, 18 –20). The diagnostic value of clonidine provocative 51– 60 yr, 41.5 mg/L between 61–70 yr, and 24.7 mg/L between 71– 80 yr.
testing is limited, whereas arginine (ARG) and glucagon Student’s paired t test and linear regression analysis were used for
alone could be useful tests but are less discriminatory than statistical analysis of the data.
Results (mean 6 sem) are expressed as absolute values for GH, as well
ITT (18, 21). Testing with GHRH alone has no diagnostic as for IGF-I (mg/L).
value (22); but when GHRH is given in combination with
ARG, it becomes the most useful, reproducible, and age- Results
independent provocative test to evaluate the maximal se-
Mean IGF-I levels were 74.6 6 8.3, with a range between
cretory capacity of somatotrope cells (10, 22, 23). In our lab,
7.0 –200.0 mg/L. Sixty-two percent of the patients had IGF-I
the third centile limit of the GH response to GHRH1ARG
levels below the age-adjusted normal range, but the percent-
test across human lifespan is 16.5 mg/L, and our previous
age was 91% for patients between 20 – 40 yr old.
data showed that it reproducibly distinguishes between nor-
The 3rd centile limit of the peak GH response to ITT was
mal and GHD adult and elderly subjects (10, 23). Based on
assumed to be 5 mg/L, based on data from literature (1, 9),
this evidence, the GHRH1ARG test has been proposed as the
whereas in our laboratory, the response to GHRH1ARG
most promising alternative to ITT for the diagnosis of GHD
provocation was 16.5 mg/L.
(11).
The mean peak GH response to ITT (1.5 6 0.2 mg/L, range
The aim of the present study was to compare the diag-
0.1– 8.5 mg/L) was lower (P , 0.001) than that to
nostic reliability of ITT and the GHRH1ARG test in a large
GHRH1ARG (3.0 6 0.4 mg/L, range 0.1–12.0 mg/L) (Fig. 1).
population of hypopituitary adults.
The peak GH responses to the two tests were positively
associated (r 5 0.61, P , 0.0001), whereas both were inde-
Subjects and Methods pendent of age. The peak GH response to GHRH1ARG (r 5
Forty adult hypopituitary patients (n 5 40; 29 male and 11 female, age: 0.35, P , 0.03) [but not the response to ITT (r 5 0.2, P not
36.4 6 2.1 yr) were studied. Among them, 21 had acquired adult onset significant)] was positively, though weakly, associated with
GHD: 13 of them had panhypopituitarism, whereas the others had 1–2 IGF-I levels. The mean peak GH responses to ITT and
deficiencies other than GH.
Nineteen patients had childhood onset (CO) GHD: eight of them had
GHRH1ARG in CO-GHD (1.3 6 0.3 and 3.0 6 0.6 mg/L,
isolated GHD, whereas the others had panhypopituitarism already di- respectively) were similar to those in adult onset-GHD (1.8 6
agnosed and treated in childhood. In CO-GHD, the diagnosis had been 0.4 and 3.1 6 0.6 mg/L, respectively). Similarly, the mean
already demonstrated in childhood by failure to respond to two classical peak GH responses in patients with panhypopituitarism
provocative tests. (1.9 6 0.7 and 2.9 6 0.8 mg/L, respectively) were similar to
The etiologies of multiple hypopituitarism other than GH (n 5 32)
were the following: 24 with pituitary tumors and craniopharingioma those in patients with one to two pituitary hormonal insuf-
before and/or after pituitary surgery or radiotherapy; 4 with idiopathic ficiencies other than GH (1.8 6 0.5 and 3.7 6 1.0 mg/L,
hypopituitarism; 2 with posttraumatic hypopituitarism; 1 with Sheehan respectively).
syndrome; and 1 with histiocytosis. Analyzing individual GH peaks, 4/40 (10%) of the patients
No patient received rhGH for at least 3 months before testing,
whereas all patients with pituitary insufficiencies other than GH had
had GH peaks higher than 5 mg/L after ITT; moreover, 3
been in optimized replacement therapy for at least 3 months with thy- other patients (7%) had GH peaks, after ITT, higher than 3
roid hormone, cortisone acetate, gonadal steroids, and (deamino-cys, mg/L (Figs. 2 and 3). On the other hand, after GHRH1ARG,
D-ARG)-vasopressin (DDAVP, desmopressin) when appropriate.
The local ethical committee approved the study protocol, and all
patients gave their informed consent to participate in the study.
All patients underwent the following tests, in the morning after an
overnight fasting, at least 3 days apart: 1) ITT (regular insulin, Actrapid
Novo-Nordisk Denmark: 0.1 U/kg iv at 0 min); and 2) GHRH (GHRH29,
GEREF, Serono, Italy; 1 mg/kg iv at 0 min) 1 ARG (ARG hydrochloride,
0.5 g/kg iv over 30 min from 0 to 130 min).
Blood samples were taken every 15 min from 215 to 190 min.
Serum GH levels were assayed at each time point by immunoradio-
metric assay (HGH-CTK, Sorin, Italy). All samples from an individual
subject were analyzed together. The sensitivity of the method was 0.15
mg/L. The inter- and intraassay coefficients of variation were 5.1–7.5%
and 2.6 –5.4%, respectively, at GH levels of 2.9 – 42.4 and 2.8 – 41.2 mg/L,
respectively. In our laboratory, the third centile limit of normal peak GH
response to GHRH1ARG from young adulthood to aging is 16.5 mg/L
(evaluated in a population of 74 normal subjects, age 20 – 80 yr) (10). For
ITT, we considered 5 mg/L as the third centile limit of normal peak GH
response, based on data in the literature. During ITT, glucose measure-
ment was performed, and a minimum plasma glucose level of 2.2
mmol/L or less was detected (9).
Serum IGF-I levels was assayed basally by RIA (Nichols Institute of
Diagnostics, San Juan Capistrano, CA) after acid-ethanol extraction, to
avoid interference by binding proteins. The sensitivity of the method FIG. 1. Mean and individual GH peaks, after ITT or GHRH1ARG, in
was 0.1 mg/L. The inter- and intraassay coefficients of variation were 40 hypopituitary patients.

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 ITT VS. GHRH1ARGININE TEST IN GHD 1617

all patients had GH peaks lower than 16.5 mg/L, whereas Discussion
21/40 (52.5%) had GH peaks higher than 3 mg/L. It is note- Our present results confirm that ITT is a reliable pro-
worthy that 73% of the patients with GH peak higher than vocative test for the diagnosis of adult GHD, and they show
3 mg/L after GHRH1ARG had GH peaks below this limit that the GHRH1ARG test is, at least, as sensitive as ITT,
after ITT (Fig. 2 and 3). provided that appropriate cut-off limits are considered. The
Because 3 mg/L is the arbitrary cut-off for ITT, the third GH response to both tests is positively correlated, but
centile limit of which is 5 mg/L, we arbitrarily considered 9 GHRH1ARG is a more potent stimulus of GH secretion than
mg/L as the cut-off point for GHRH1ARG. It is noteworthy ITT, even in GHD patients. Moreover, the GH response to
that 37/40 (92.5%) of the patients had GH peaks, after GHRH1ARG, but not that to ITT, is positively associated
GHRH1ARG, below this limit (including 6/7 patients with with IGF-I levels.
GH peaks more than 3 mg/L after ITT (Figs. 2 and 3). Note There is consensus that the diagnosis of adult GHD is
that those patients with GH peaks higher than 3 mg/L after established by provocative testing of GH secretion (9 –10).
ITT or 9 mg/L after GHRH1ARG had multiple pituitary ITT is considered the test of choice (9, 11, 12). In fact, this test
insufficiencies. has been found to be capable of distinguishing GHD from the
No significant side effects were observed with both tests. reduced GH secretion that accompanies aging and obesity.
Only mild tachycardia and sweating (after ITT) and transient Following consensus of opinion leaders (11, 12), severe GHD,
facial flushing (after GHRH) occurred in the majority of to be treated with rhGH replacement, is defined by an ar-
patients. However, no test had to be stopped. bitrary cut-off that is a GH peak response to ITT less than 3
mg/L. Note that the lowest limit of GH response to ITT in
normal individuals has been reported as 5 mg/L (9). How-
ever, recently, ITT has been found to be poorly reproducible
in normal subjects, thus questioning its specificity (16, 17).
Moreover, ITT is contraindicated in patients with ischemic
heart disease, seizure disorders, and aging (12).
Alternative provocative tests of GH secretion have been
proposed, but they must be used with appropriate cut-off
limits (11, 12). Among alternatives, other classical provoca-
tive tests, as well as GHRH alone, are of less (if any) value,
when compared with ITT (18, 21, 22). However, when GHRH
is given in combination with ARG or pyridostigmine, which
probably act via inhibition of hypothalamic somatostatin
release (24), it becomes the most potent and reproducible
provocative test to evaluate the pituitary GH releasable pool
(19, 20, 22, 23, and present data) distinguishing between
normal and GHD adults (10, 20).
In contrast to GHRH1PD, the GH response to
FIG. 2. Correlation between individual peak GH responses to GHRH1ARG is not reduced in aging (25–27). Thus, it has
GHRH1ARG and ITT tests in 40 adult GHD patients (r 5 0.6, P , been suggested that the latter stimulus could be proposed as
0.001). the most promising alternative to ITT.

FIG. 3. Peak GH response to ITT or

GHRH1ARG in the same adult pa-
tients with GHD (n 5 40).

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1618 AIMARETTI ET AL. JCE & M • 1998
Vol 83 • No 5

With respect to its third centile cut-off limit (5.0 mg/L GH 2. Jorgensen JOL, Theusen L, Ingemann-Hansen T, et al. 1989 Beneficial effects
of growth hormone treatment in GH-deficient adults. Lancet. i:1221–1225.
peak) (9), ITT demonstrated GHD in 90% of the patients, 3. Salomon F, Cuneo RC, Hesp RC, Sonksen PH. 1989 The effects of treatment
whereas all of them had insufficient GH response to with recombinant human growth hormone on body composition and metab-
GHRH1ARG. This picture overlaps with that comparing ITT olism in adults with growth hormone deficiency. N Engl J Med. 321:1979 –1983.
4. Cuneo RC, Salomon F, Mark Wiles C, Hesp RC, Sonksen PH. 1991 Growth
with GHRH 1 pyridostigmine in a large population of young hormone treatment in growth hormone deficient adults. II. Effects on exercise
and middle-aged GHD subjects (20). performance. Am J Physiol. 70:695–700.
With respect to the arbitrary cut-off of 3 mg/L as the limit 5. Amato G, Carella C, Fazio S, et al. 1993 1993 Body composition, bone me-
tabolism and heart structure and function in growth hormone (GH) deficient
below which severe GHD is demonstrated after ITT (11, 12), adults before and after GH replacement therapy at low doses. J Clin Endocrinol
83% of the patients were below this limit. Thus, our data Metab. 77:1671–1676.
confirm the diagnostic reliability of ITT, which, in our hands, 6. Merola B, Cittadini A, Colao A, et al. 1993 Cardiac structural and functional
abnormalities in adult patients with growth hormone deficiency. J Clin En-
gave no serious side effects. docrinol Metab. 77:1658 –1663.
On the other hand, with respect to the arbitrary cut-off of 7. Cittadini A, Cuocolo A, Merola B, et al. 1994 Impaired cardiac performance
3 mg/L, 47.5% of the patient population has peak GH results in GH-deficient adults and its improvement after GH replacement. Am J
Physiol. 267:E219 –E225.
below this limit when tested with GHRH1ARG. Note that 8. Rosen T, Bengtsson BA. 1990 Premature mortality due to cardiovascular
73% of them had had a GH peak lower than 3 mg/L after ITT. disease in hypopituitarism. Lancet. 336:285–288.
Theoretically, one could hypothesize that ITT had given a 9. Hoffman DM, O Sullivan AJ, Baxter RC, Ho KY. 1994 Diagnosis of growth
hormone deficiency in adults. Lancet. i:1064 –1068.
large number (approximately 50%) of false positive re- 10. Ghigo E, Aimaretti G, Gianotti L, Bellone J, Arvat E, Camanni F. 1996 New
sponses, indicating severe GHD. However, this hypothesis is approach to the diagnosis of growth hormone deficiency in adults. Eur J
unlikely, considering that the majority of these patients had Endocrinol. 134:352–356.
11. Growth Hormone Research Society (GRS). 1998 Consensus guidelines for
multiple pituitary insufficiencies and low IGF-I levels. diagnosis and treatment of adults with GH deficiency. Porth Stephens work-
We would like to emphasize that each test must be used shops April 1997. J Clin Endocrinol Metab. 83:379 –381.
12. Thorner MO, Bengtsson BA, Ho KKY, et al. 1995 Diagnosis of growth hor-
with appropriate cut-off limits. This means also that the mone deficiency in adults. J Clin Endocrinol Metab. 80:3097–3098.
arbitrary cut-off point below which severe GHD is demon- 13. Svensson J, Johannsson G, Bengtsson BA. 1997 Insulin-like growth factor-I
strated has to be appropriate to the potency of each provoc- in growth hormone-deficient adults: relationship to population-based normal
value, body composition and insulin tolerance test. Clin Endocrinol (Oxf).
ative test. Because 3 mg/L is the arbitrary cut-off for ITT, the 46:579 –586.
third centile limit of which is 5 mg/L, we arbitrarily consid- 14. Reutens AT, Hoffmann DM, Leung K, Ho KKY. 1995 Evaluation and ap-
ered 9 mg/L as the cut-off point for GHRH1ARG; note that plication of a highly sensitive assay for serum growth hormone (GH) in the
study of adult GH deficiency. J Clin Endocrinol Metab. 80:480 – 485.
this limit represents the first centile limit of the normal GH 15. Jones SL, Trainer PJ, Perry L, Wass JAH, Besser GM, Grossman A. 1994 An
response to the GHRH1ARG test, in a large population of audit of the insulin tolerance test in adult subjects in an acute investigation unit
normal subjects (10). over one year. Clin Endocrinol (Oxf). 41:123–128.
16. Hoeck HC, Vestergaard P, Jakobsen PE, Laurberg P. 1995 Test of growth
Note that 92.5% of the GHD patients had GH peaks, after hormone secretion in adults: poor reproducibility of the insulin tolerance test.
GHRH1ARG, below the limit of 9 mg/L. This population Eur J Endocrinol. 133:305–312.
also included 6/7 of the patients with GH peaks higher than 17. Vestergaard P, Hoeck HC, Jakobsen E, Laurbarg P. 1997 Reproducibility of
growth hormone and cortisol responses to the insulin tolerance test and the
3 mg/L after ITT. We concluded that all these patients have short ACTH test in normal adults. Horm Metab Res. 29:106 –110.
severe GHD; they are all now treated with rhGH and show 18. Rahim A, Toogood, Shalet SM. 1996 The assessment of growth hormone in
benefit from treatment. normal young adult using a variety of provocative agents. Clin Endocrinol
(Oxf). 45:557–562.
On the other hand, we assumed that patients with GH 19. Longobardi S, Merola B, Pivonello R, et al. 1996 Re-evaluation of growth
peaks higher than 9 mg/L (7.5%), but lower than 16.5 mg/L, hormone (GH) secretion in 69 adults diagnosed as GH-deficient patients dur-
after GHRH1ARG had partial GHD. At present, there is no ing childhood. J Clin Endocrinol Metab. 81:1244 –1247.
20. Andersen M, Hansen TB, Stoving RK. 1996 The pyridostigmine-growth-
evidence supporting the hypothesis that partial GHD in hormone-releasing-hormone test in adults. The reference interval and a com-
adults needs GH replacement. parison with the insulin tolerance test. Endocrinol Metab. 3:197–206.
Finally, we would like to emphasize that, unlike ITT, the 21. Baum HBA, Biller BMK, Katznelson L, et al. 1996 Assessment of growth
hormone (GH) secretion in men with adult-onset GH deficiency with that in
GH response to GHRH1ARG in GHD is positively associ- normal men - a clinical research study. J Clin Endocrinol Metab. 81:84 –92.
ated with IGF-I levels, which is the best marker of GH se- 22. Ghigo E, Bellone J, Aimaretti G, et al. 1996 Reliability of provocative tests to
assess growth hormone secretory status. Study in 472 normally growing chil-
cretory status (28). This evidence reinforces the reliability of dren. J Clin Endocrinol Metab. 81:3323–3327.
this provocative test for the diagnosis of severe adult GHD. 23. Valetto MR, Bellone J, Baffoni C, et al. 1996 Reproducibility of the growth
In conclusion, our present results show that the hormone response to stimulation with growth hormone-releasing hormone
plus arginine during lifespan. Eur J Endocrinol. 135:568 –572.
GHRH1ARG test is, at least, as reliable as ITT for the di- 25. Ghigo E. 1992 Neurotransmitter control of growth hormone secretion. In: De
agnosis of adult GHD, provided that appropriate cut-off la Cruz LF, ed. Regulation of growth hormone and somatic growth. Amster-
limits are considered. dam: Elsevier Science Publishers; 103–136.
25. Ghigo E, Goffi S, Nicolosi M, et al. 1990 Pyridostigmine partially restores the
GH responsiveness to GHRH in normal aging. Acta Endocrinol (Copenh).
Acknowledgments 123:169 –174.
26. Ghigo E, Goffi S, Nicolosi M, et al. 1990 Growth hormone (GH) responsive-
The authors wish to Dr. J. Bellone, E. Ciccarelli, and G. Sortino for their ness to combined administration of arginine and GH-releasing hormone does
cooperation in the study; and Mrs. M. Taliano for her skillful technical not vary with age in man. J Clin Endocrinol Metab. 71:874 – 876.
assistance. 27. Ghigo E, Nicolosi M, Arvat E, et al. 1994 Growth hormone secretion in
Alzheimer’s disease: studies with growth hormone releasing hormone alone
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