THERAPEUTIC CONTROVERSY
clude that quality of life is significantly reduced we offer a
therapeutic trial of GH replacement. This involves an initial
period of 2–3 months to titrate the appropriate GH dose
using insulin-like growth factor I SDS measurements and
lack of side effects, followed by a 6-month therapeutic trial
with the selected dose. Since we adopted the policy of initiating GH replacement with a low dose, independent of size
or weight, side effects have been reduced dramatically
(24, 25).
Other authors (26) have suggested that physiological GH
replacement may not result in an improvement in quality of
life, and they have proposed that the benefits observed in
earlier studies were related to the use of supraphysiological
GH doses associated with abnormally elevated insulin-like
growth factor I levels (26). With our strategy of selecting
patients based on a patient perceived impairment in quality
of life, generic and disease-specific questionnaire data have
shown a greater degree of impairment of quality of life at
baseline and a greater response to GH replacement than
previously published studies in unselected GH-deficient
adults (24). Within our cohort of 65 patients it has been
demonstrated that the degree of improvement in quality of
life is dependent on the level of impairment of quality of life
before commencement of GH replacement (24). The real reason for the negative findings of Baum et al. (26) is the unselected study cohort rather than the dose of GH.
The above policy applies to the adult onset GHD patient
or the childhood onset GHD patient who stopped GH replacement at the end of linear growth a number of years
earlier. For the GHD teenager who is approaching completion of linear growth, it remains unsettled as to whether or
not he or she should continue on GH replacement seamlessly
through adult life or if he or she could stop GH for a few years
without being placed at an irreversible disadvantage (i.e.
acquisition of peak bone mass). At the same time, it is also
unclear when such an individual should be switched from
the typical pediatric to the adult GH replacement dose schedule. There are also no disease-specific quality of life measures
devised for this age group. It is my view that we need multicenter studies to determine the optimal strategy for replacing GH in this particular situation.
The first documented studies (27, 28) of GH replacement
in adults with GHD were reported in 1989, and we have
learned an enormous amount over the last 9 yr, but we are
not yet in a position to justify an offer of GH replacement to
all adults with severe GHD on a routine basis.
References
1. Salomon F, Cuneo RC, Hesp R, Sonksen PH. 1989 The effects of treatment
with recombinant growth hormone on body composition and metabolism in
adults with growth hormone deficiency. N Engl J Med. 321:1797–1803.
2. DeBoer H, Blok GJ, Voerman HJ, DeVries PMJM, Van der Veen EA. 1992
Body composition in adult growth hormone deficient men, assessed by anthropometry and bioimpedance analysis. J Clin Endocrinol Metab. 75:833– 837.
3. Libber SM, Plotnick LP, Johanson AJ, Blizzard RM, Kwiterovich PO, Migeon CJ. 1990 Long-term follow-up of hypopituitary patients treated with
human growth hormone. Medicine. 69:46 –55.
4. Cuneo RC, Salomon F, Watts GF, Hesp R, Sonksen PH. 1993 Growth hormone
treatment improves serum lipids and lipoproteins in adults with growth hormone deficiency. Metabolism. 42:1519 –1523.
5. Johansson JO, Landin K, Tengborn L, Rosén T, Bengtsson BA. 1994 High
fibrinogen and plasminogen activator inhibitor activity in growth hormone
deficient adults. Arterioscler Thromb. 14:434 – 437.
939
6. Johansson JO, Fowelin J, Landin K, Lager I, Bengtsson BA. 1995 Growth
hormone deficient adults are insulin resistant. Metabolism. 44:1126 –1129.
7. Longobardi S, Cuocolo A, Merola B, et al. 1998 Left ventricular function in
young adults with childhood and adulthood onset growth hormone deficiency. Clin Endocrinol. 48:137–144.
8. Beshyah SA, Shahi M, Mayet J, Foale R, Johnston DG. 1996 Growth hormone
and the cardiovascular system. In: Ranke M, Christiansen JS, eds. The complexity of endocrine systems. Mannheim: J & J-Verlag; 131–155.
9. Markussiś V, Beshyah SA, Fisher C, Sharp P, Nicolaides AN, Johnston DG.
1992 Detection of premature atherosclerosis by high-resoluation ultrasonography in symptom-free hypopituitary adults. Lancet. 340:1188 –1192.
10. Rosen T, Bengtsson B-A. 1990 Premature mortality due to cardiovascular
disease in hypopituitarism. Lancet. 336:285–288.
11. Bulow B, Hagmar L, Mikoczy Z, Nordstrom CH, Erfurth EM. 1997 Increased
cerebrovascular mortality in patients with hypopituitarism. Clin Endocrinol.
46:75– 81.
12. Johannsson G, Rosén T, Bosaeus I, Sjostrom L, Bengtsson B-A. 1996 Longterm growth hormone treatment increases bone mineral content and density
in patients with adult-onset growth hormone deficiency. J Clin Endocrinol
Metab. 81:2865–2873.
13. Brennan BMD, Rahim A, Mackie EM, Eden OB, Shalet SM. 1998 Growth
hormone status in adults treated for acute lymphoblastic leukaemia in childhood. Clin Endocrinol (Oxf). 48:777–783.
14. Hoffman DM, O’Sullivan AJ, Baxter RC, Ho KY. 1994 Diagnosis of growth
hormone deficiency in adults. Lancet. 343:1064 –1068.
15. Bates AS, Bullivant B, Clayton RN, Sheppard MC, Stewart PM. 1997 Increased mortality in hypopituitarism is not due to an increase in vascular
mortality. J Endocrinol. 152 (Suppl): OC9.
16. Eden S, Wiklund O, Oscarsson J, Rosén T, Bengtsson BA. 1993 Growth
hormone treatment of growth hormone deficient adults results in a marked
increase in Lp(a) and HDL cholesterol concentrations. Arterioscler Thromb.
13:296 –301.
17. Rosen T, Eden S, Larson G, Wilhemsen L, Bengtsson B-A. 1993 Cardiovascular risk factors in growth hormone deficient adults. Acta Endocrinol.
129:195–200.
18. Kaji H, Abe H, Fukase M, Chihara K. 1997 Normal bone mineral density in
patients with adult onset GH deficiency. Endocrinol Metab. 4:163–166.
19. Toogood AA, Adams JE, O’Neill PA, Shalet SM. 1997 Elderly patients with
organic growth hormone (GH) deficiency are not osteopenic. J Clin Endocrinol
Metab. 82:1462–1466.
20. Holmes SJ, Shalet SM. 1995 Characteristics of adults who wish to enter a trial
of growth hormone replacement. Clin Endocrinol (Oxf). 42:613– 618.
21. Holmes SJ, Shalet SM. 1995 Factors influencing the desire for long term
growth hormone replacement in adults. Clin Endocrinol (Oxf). 43:151–157.
22. Rosén T, Wiren L, Wilhelmsen L, Wiklund I, Bengtsson B-A. 1994 Decreased
psychological well-being in adult patients with growth hormone deficiency.
Clin Endocrinol (Oxf). 40:111–116.
23. McKenna SP, Doward LC. 1994 Quality of life assessment of adults with
growth hormone deficiency. Implications for drug therapy. Pharmaco-Econ.
6:434 – 441.
24. Murray RD, Skillicorn CJ, Howell SJ, Lissett CA, Rahim A, Shalet SM. 1999
Dose titration and patient selection increases the efficacy of GH replacement
in severely GHD adults. Clin Endocrinol (Oxf). 50:749 –757.
25. Drake WM, Coyte D, Camacho-Hubner C, et al. 1998 Optimizing growth
hormone replacement therapy by dose titration in hypopituitary adults. J Clin
Endocrinol Metab. 83:3913–3919.
26. Baum HBA, Katznelson L, Sherman JC, et al. 1998 Effects of physiological
growth hormone (GH) therapy on cognition and quality of life in patients with
adult onset GH deficiency. J Clin Endocrinol Metab. 83:3184 –3189.
27. Jorgensen JOL, Pedersen SA, Thuesen L, et al. 1989 Beneficial effects of
growth hormone treatment in GH-deficient adults. Lancet. 1:1221–1225.
28. Salomon F, Cuneo RC, Hesp R, Sönksen PH. 1989 The effects of treatment
with recombinant human growth hormone on body composition in adults with
growth hormone deficiency. N Engl J Med. 321:1797–1803.
Treatment of Growth Hormone Deficiency in Adults
Helen Simpson and Peter Sonksen
Department of Endocrinology
St. Thomas’ Hospital
London SE1 7EH, United Kingdom
“The regimen I adopt shall be for the benefit of patients
according to my ability and judgement . . .”
From the Hippocratic oath— c. 4th Century B.C.
940
THERAPEUTIC CONTROVERSY
G
H DEFICIENCY (GHD) in adults is now well defined
both clinically and biochemically. With the advent of
recombinant technology there is now a virtually unlimited,
safe supply of recombinant human GH for treatment of children and adults with GHD. Anyone who has prescribed GH
replacement therapy can tell anecdotal reports of patients
lives (and indeed the lives of their families) who were completely transformed by GH replacement, and there is a
wealth of data showing GH replacement ameliorates the
most prominent features of GHD (alterations in body composition, reduced energy and work capacity, and impaired
psychological well being) over the short term by GH replacement. However, in these days of evidence-based medicine, especially where governments are rationing health
care, it is becoming harder to obtain funding for expensive
drugs. The authors of both the previous articles agree that the
published evidence supports short-term GH replacement in
at least some adults with severe GHD. There are, however,
several questions that remain to be answered.
1. Are there benefits of long-term hormone replacement
therapy with GH?
Evidence to support long-term GH replacement is becoming available. It is now 10 yr since the initial studies of GH
replacement and a 10-yr follow-up study of one of the original cohorts [the St. Thomas’ cohort studied by Salomon et al.
(1)] has been published recently in this journal. Gibney et al.
(2) traced and restudied 21 of the original cohort, 10 of whom
had been treated with GH for the entire 10 yr (the reasons
why only 50% continued to take GH were mainly “local
medico-political-funding” issues rather than patient preferences. The treated and nontreated groups did not differ measurably). The results showed that the benefits of GH in terms
of altered body composition, an improved lipid profile, and
improved psychological well being measured using the Nottingham Health Profile were maintained and were significantly improved compared to the group who had not received long-term GH treatment. In addition, there was
evidence indicating reduced development of atherosclerosis
(as measured by carotid intimal thickness), no increase in left
ventricular wall thickness or hypertension, and no decrease
in insulin sensitivity (as shown by measurements of fasting
insulin and glucose). The conclusions reached were that the
benefits gained in the initial study were maintained over 10
yr with no worsening of the cardiovascular status of the
GH-treated group, indeed to the contrary that the GHtreated group showed long-term benefits from continued
replacement therapy, evidence that they benefited.
This is the first long-term study to be published, however,
it only involved a small number of patients and it is not a true
prospective randomized controlled trial but rather “randomization by NHS lottery.” True randomized long-term controlled trials will not and cannot be done because GH replacement has been shown to offer so many short- and
medium-term advantages that no ethics committee would
accept randomization to no GH replacement and no wellinformed patient would accept to be randomized. There remains no evidence, however, that long-term GH replacement
reverses the observed increase in mortality, especially from
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cardiovascular causes, or reduces the increased fracture rate
seen in GHD. These questions can only be answered by
properly designed long-term prospective studies of GH replacement. Who is going to do these?
2. Is long-term GH replacement therapy safe?
The major concerns regarding the safety of long-term GH
replacement are those of effects on the cardiovascular system
(increased left ventricular hypertrophy and possible increased insulin resistance, which offsets improvements in
central adiposity), the possibility of an increase in malignant
tumors, and the recurrence of pituitary tumors. Data from
the 10-yr follow-up study did not indicate any adverse effects
of long-term GH treatment. Specifically, there was no increase in vascular events in the GH-treated group, no worsening of insulin sensitivity, no increase in left ventricular
wall thickness or hypertension, no recurrence of pituitary
tumors, and no new malignancies reported.
Although there are and never will be long-term prospective placebo-controlled studies, there have been attempts to
collect long-term data of GH replacement. Each of the major
manufacturers of GH have initiated “postmarketing surveillance” databases to monitor the safety of GH replacement in
adults, NovoNordisk with Nordireg, Genentech with the
NCSS database, Lilly with HypoCCS, and Pharmacia with
KIMS. To date, KIMS has the largest number of patients on
record with data from 4200 patients and details from 25
different countries. At the present time there seems to be no
increase in adverse events. There has recently been reported,
however, a possible small increase in de novo malignancies,
leukemias and lymphomas, the significance of which is unknown. This comes at a time when there is much debate
about the interpretation of epidemiological evidence showing a link between serum insulin-like growth factor (IGF) I
levels and the prevalence of cancer of the breast and prostate
in people without GHD. In view of the fact that malignancy
rates in long-standing acromegaly are only marginally
raised, it is not clear what the significance of these epidemiological and KIMS findings is, unclear but not unduly
disturbing. It is, however, another example of the reason why
it is essential to monitor patients on GH carefully and to build
collaborative databases to accumulate longitudinal experience. Although such individual company databases are a
useful surveillance tool, it is unlikely that this somewhat
fragmented approach will ever have the statistical power to
be able to provide the long-term safety data that we all need.
What is really needed is a properly designed prospective
epidemiological study gathering information about those not
receiving GH as well as those on GH with collaboration
between endocrinologists, epidemiologists, and the pharmaceutical industry. The Growth Hormone Research Society
(GRS) is in an ideal position to facilitate this because it has
good relations with and sponsorship from all the appropriate
industries. It has already shown its ability to bring people
together in two excellent Consensus Workshops (Port Stephens in 1997 and Elat in 1999) and a workshop on “Safety”
is planned for the spring of 2000. The GRS now needs to show
strong leadership in the development of a professional col-
THERAPEUTIC CONTROVERSY
laborative epidemiological study capable of answering the
key safety issues speedily and unambiguously.
3. What is the best method of monitoring clinical and
biochemical response?
There is no ideal marker for monitoring GH replacement.
Although changes in body composition are the most striking
and consistent finding in studies of GH replacement, changes
in individual patients (and in health) vary greatly. Attempts
to achieve normal body composition with GH replacement
can result in IGF-I levels well above the age-related normal
range and clinical evidence of GH excess. IGF-I is the most
sensitive serum marker, having been repeatedly shown to be
more sensitive to GH excess than the GH-dependent peptides ALS and IGFBP-3, as well as responding more rapidly
to changes in GH dose. However, IGF-I can still be inside the
age-related normal range in patients with clear clinical evidence of GH excess, particularly in the face of conditions with
low portal insulin concentrations (e.g. Type 1 diabetes, malnutrition, and malabsorbtion syndromes) or liver disease.
Also IGF-I is not a marker of tissue effectiveness to GH. It is
possible that circulating GH-sensitive markers of collagen
and bone, such as procollagen 3 peptide terminal extension
peptide (P-III-P) and osteocalcin may prove more valuable in
this regard.
Until such a time that a better marker of GH replacement
becomes available, IGF-I and body composition, together
with a clinical assessment of the patient, focusing specifically
on the quality of life issues that have been shown to be most
characteristic of GHD (including energy, mood, social isolation, and self-control) taken with a partner’s assessment
where available remain the best way of monitoring GH replacement therapy.
4. In view of the somatopause, until what age should
GH be given?
There is no evidence to suggest that elderly patients with
organic GHD should be denied GH replacement. Although
there are difficulties in diagnosing GHD using the insulin
tolerance test in elderly patients who may have silent myocardial disease, organic GHD can be distinguished from the
somatopause by the presence of pituitary pathology and by
using other provocation tests, such as arginine or GHRH
(⫹/⫺ GH releasing peptide). In all patients, but particularly
the elderly, GH should be started at a low dose and titrated
gradually with serum IGF-I levels kept within the age-related
normal range. Patients should be monitored carefully for
clinical evidence of GH excess because this group is particularly susceptible to effects of GH excess.
In many ways, old age itself is similar to many features of
adult onset GHD. Aging results in an increase in body fat
(particularly central abdominal fat), loss of muscle mass,
reduced strength, and reduced bone density, together with
a decrease in GH secretion. Rudman’s original contribution
to research into GH and aging in the early 1980s remains of
great importance. He was remarkably perspicacious in predicting the importance of failing GH secretion in the changes
in body composition seen with aging and in pioneering pilot
trials showed beneficial effects of GH replacement on body
941
composition and bone density. This and other studies raises
the important question: “Would GH replacement be beneficial for the elderly population, in general, or in particular
those with frailty?” There is a clear need for multicenter
studies investigating long-term GH replacement in the frail
elderly with end points such as the ability to perform activities of daily living and the ability to maintain independence.
Once there is “proof of concept” that GH replacement is able
to maintain (or rebuild?) significant amounts of lean tissues
in this population, the development of oral GH secretagogues may mean that in the future GH hormone replacement will become similar to traditional oestrogen hormone
replacement in postmenopausal women. Obviously, much
more research is needed, but the number of older adults
worldwide is increasing, and so the burden on health care
provision is increasing and this form of hormone replacement offers a potentially powerful way of mitigating the
burden and improving the quality of life of all of us. A drug
that may help prevent falls and ameliorate frailty would be
very attractive, and cost-effective in cash-strapped health
services.
5. Is GH replacement cost-effective?
Health care in the Western world as we approach the new
millennium is expensive, consuming between 6 and 12% of
the gross national product of industrialized nations. In the
United Kingdom for the year 1997/1998, some £505 million
of that was spent on drugs. GH replacement is not cheap at
a cost of about $5,000 (£3,500) per year, but neither is it
expensive in comparison to, say, the cost of triple therapy for
HIV-positive patients at $12,800 (£8,000) per year. Adult
GHD has prevalence of about 15 in 100,000 in the United
Kingdom. Assuming that not all of these patients tolerate or
would like GH replacement, and we estimate that 50% of
them are treated with GH replacement, then the cost would
be $1.6 million (£1 million) per year, or 0.2% of the annual
National Health Service drug budget. This cost varies between individual countries as the percentage of patients receiving GH replacement varies considerably; for example,
Sweden has a much higher rate of GH replacement in its
GH-deficient adults. It has already been shown that GH
replacement in adults leads to a significant improvement in
well-being, quality of life, energy level, and work capacity,
resulting in a proportion of patients being able to return to
work, or to work more effectively. If long-term treatment
with GH is shown, in addition, to result in a decrease in
premature mortality rate with decreased cardiovascular
events and bone fractures then GH will be most likely be
shown to be cost-effective. GH replacement could become
even more cost-effective if it was introduced successfully as
an antifrailty treatment in the older general population, preventing the morbidity and mortality associated with falls and
frailty in this age group.
It should also be mentioned that in the 10 yr follow-up
study although 10 of the original patients randomized to
receive GH were included in the follow-up study only 5 of
these were still on GH replacement. Some of the other five
patients were not able to continue GH because funding was
denied by their local health authority, an example of how
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THERAPEUTIC CONTROVERSY
despite the political statements saying the contrary, in the
United Kingdom health rationing already takes place. It does
seem that in many developed countries patients with adult
onset GHD are being denied access to appropriate hormone
replacement purely on the basis of cost.
As endocrinologists we would probably all agree that
there is a place for, at the very least, a trial of GH replacement
for all our patients with GHD. In addition, there are exciting
possibilities that in the future GH may become more widely
useful. It remains crucial, however, that GH treatment is
monitored closely both within the individual and also on a
larger to scale to answer some of the outstanding questions
about efficacy and safety. The existing methods of doing this
are inadequate, and the relevant industries should demonstrate their ability to cooperate with each other and with the
Growth Hormone Research Society and set up a collaborative
prospective study with sufficient power to be able to answer
these key questions within a reasonable time frame.
References
1. Salomon F, Cuneo R, Hesp R, Sonksen PH. 1989 The effects of treatment with
recombinant human growth hormone on body composition and metabolism
in adults with growth hormone deficiency. N Engl J Med. 321:1797–1803.
2. Gibney J, Wallace JD, Spinks T, et al. 1999 The effects of 10 years of recombinant human growth hormone (GH) in adult GH-deficient patients. J Clin
Endocrinol Metab. 84:2596 –2602.