The anterior pituitary hormone somatotrophin has an important
regulatory action on all body tissues often mediated via its stimulatory
effects on the growth factor IGF-1. Its trivial name, growth hormone, derives
from just one aspect of these actions, that is the promotion of linear growth
in children. Somatotrophin deficiency is a virtually invariable component
of hypopituitarism.
Epidemiology
Somatotrophin deficiency in adults results from decreased production
of somatotrophin from the anterior pituitary gland. It usually occurs as
a consequence of a structural pituitary disease or peripituitary lesion,
eg. pituitary adenoma (1), or as a result of treatment eg. cranial irradiation
(2), surgery. It is estimated that the prevalence of adult onset somatotrophin
deficiency is 1 in 10,000 of the population. If adult deficiencies commencing
in childhood are also considered the prevalence may be nearer 3 in 10,000.
Childhood isolated somatotrophin deficiency is usually caused
by a partial deficiency of growth hormone releasing hormone (GHRH). The deficiency
does not always continue into adulthood, possibly due to maturation of the
hypothalamic/somatotrophin axis. Children therefore need to be reviewed and
retested once their final height has been reached.
Consequences of somatotrophin deficiency (3)
Symptoms
Decreased energy levels
Social isolation
Lack of positive well being
Depressed mood
Increased anxiety
Clinical features
Increased body fat, particularly central adiposity.
Decreased muscle mass.
Decreased bone density, associated with an increased risk
of fracture.
Increased LDL cholesterol and Apo B. Decreased HDL cholesterol.
Decreased cardiac muscle mass (especially in childhood onset
somatotrophin deficiency
Impaired cardiac function.
Decreased total and extracellular fluid volume.
Decreased insulin sensitivity (4) and increased prevalence
of impaired glucose tolerance.
Increased concentration of plasma fibrinogen and plasminogen
activator inhibitor type I (5).
Accelerated atherogenesis (6,7).
The above metabolic changes are likely to increase the risk
of atheromatous cardiovascular disease and decrease physical performance.
This is borne out by retrospective analyses of epidemiological data which
show that hypopituitary patients have approximately double the risk of cardiovascular
death (1,8). Conclusive evidence that this is due to somatotrophin deficiency
is, however, lacking although therapy with somatotrophin reverses most of
the metabolic changes associated (in other studies) with increased cardiovascular
risk.
Diagnosis
The diagnosis of somatotrophin deficiency is made by measuring
serum GH concentrations in response to dynamic test(s). The gold standard
is the insulin tolerance test (ITT) (9). Earlier published studies used different
serum GH cut offs for the diagnosis, ranging from <3mu/l to < 15mu/l
and were bedevilled by wide variation in the results from different commercial
assays (10). A consensus has now been reached which states that a level of
GH < 9mu/l in response to hypoglycaemia is diagnostic of severe somatotrophin
deficiency in patients with structural pituitary disease and/or other pituitary
deficiencies and/or a history of childhood GHD. However, each endocrine unit
investigating hypopituitary patients should be aware of different values
to be asked resulting from assay variations. For patients in whom ITT is
contraindicated glucagon is used (11). The test must be carried out by experienced
staff in a specialised unit.
Although it is known that increasing age can decrease GH secretary
reserve, the relative deficiency is not sufficient to obscure a diagnosis
of somatotrophin deficiency. Severe obesity may be associated with marked
reduction in GH reserve so that a diagnosis of GHD in markedly overweight
patients should be supported by additional pituitary hormone deficiency and/or
structural pituitary disease.
Clinical efficacy of growth hormone supplementation
From a review of the published literature the following conclusions
can be reached:
Overall, at least 80% of patients given growth hormone replacement
demonstrate a significant improvement, especially in fat distribution,
body composition and parameters reflecting well being and quality of life.
Potentially the greatest immediate indication for growth
hormone supplementation is in patients who are assessed as having impaired
quality of life (QOL). The early high-dose, placebo-controlled trials suggest
that around 50% of these patients demonstrated significant improvement
and a desire to continue with replacement longer term. The greatest benefit
was shown in patients who have severe somatotrophin deficiency and greater
distress in terms of energy and vitality prior to commencing growth hormone.
More recent experience using lower doses, with fewer side effects, indicate
clear improvement with patients wish to continue of about 80%.
A 6 month course of treatment is usually needed before the benefits can be
assessed clearly, although many patients show a substantial improvement in
QOL within 3 months (12,13)
It is estimated by WHO criteria that patients with a bone
mineral densitv of -1 S.D. have a 2.5 fold increased risk of a fracture.
Osteopenia in excess of this appears to be common in adult somatotrophin
deficiency. Published studies of adults on somatotrophin replacement show
that markers of bone remodelling are increased within 6 months treatment
(14). After 12 months treatment an increase in bone density can be demonstrated
(15). Recent studies show this increase to be sustained at 2 years and
beyond. Long term clinical follow up will demonstrate whether this increase
in bone density results in a significant decrease in fracture rate.
A number of studies document somatotrophin replacement to
result in a reduction of LDL cholesterol, and increase in HDL cholesterol.
This represents an improvement in cardiac risk profile. Some studies have
demonstrated small incremental rises in serum lipoprotein
(a) in patients who have otherwise demonstrated an improvement in lipoprotein
profiles(16,17).
Somatotrophin produces a significant redistribution of body
mass, decreasing body fat, central fat and waist:hip ratio and increasing
muscle mass. Body fluid balance is also restored. These benefits can be
demonstrated by many patients within 3 months of commencing GH and constitute
a potential additional improvement in cardiac risk profile.
Recommended criteria for selecting patients for growth hormone
replacement
Defined somatotrophin deficiency with ITT or glucagon tests
Peak GH < 9mu/I following ITT
Peak GH < 9mu/I following glucagon test.
Patient already receiving full supplementation of other
deficient hormones as required.
Clinical features of somatotrophin deficiency.
Severely decreased QOL as assessed using the Adult growth
hormone deficiency assessment (AGHDA) questionnaire.
and/or
Reduced bone density of < -1 S.D which by WHO criteria would predict a
relative fracture risk of > 2.5.
and/or
Reduced exercise tolerance and adverse cardiovascular risk profile.
and/or
Cardiac decompensation
Dosing
The doses used in published studies vary widely. Recent evidence
suggests that patients can now be managed on much lower doses than those
used previously. Patients are commenced on 0.8iu somatotrophin subcutaneously
once a day initially (0.4 iu may be used in patients with impaired glucose
tolerance or hypertension). The dose is reviewed every 4 weeks, according
to clinical response, serum IGF-1 and side effects. This results in a median
dose of approximately 1.2iu daily. It is empirically sensible to aim for
a serum IGF-1 between the median and upper end of a related reference range.
Side effects
The main side effects reported are arthralgia, oedema, mild
hypertension and carpal tunnel syndrome. These are believed to result from
the correction of fluid balance. They are more frequent at the higher doses
used in the earlier studies and are uncommon when the dose is carefully titrated
from a low starting dose (18). Benign intracranial hypertension has rarely
been reported but is unlikely to complicate titrated dose regimens. Nevertheless
persistent severe headaches necessitate investigation. In many patients with
somatotrophin deficiency and essential hypertension, GH replacement improves
blood pressure. This is probably because of a reduction in peripheral vascular
resistance.
Cost of treating
Lowest dose
0.4iu/day
Costs £l, 112 pa
Median dose
1.2iu/day
Costs £3,453 pa
Maximum dose
3.6iu/day
Costs £11,220 pa
The above are costs for the GP to prescribe, using MIMS price
and assuming a 21-day shelf life of a cartridge in the refrigerator once
opened. Patients receiving a dose of 0.8iu daily or above use a 16iu cartridge
with an automated pen device. Patients receiving low doses of less than 0.8iu
daily use a 4iu cartridge as it ismore economical.
If 80% of adult-onset somatotrophin deficiency patients were
to require treatment with somatotrophin in the long term, this equates to
around 8 patients out of 100,000 population. For a population of 750,000
the cost of providing a median dose to all patients can be estimated as £208,000
pa. This does not include treatment of persisting childhood-onset somatotrophin
deficiency
Cost of not treating
This is very difficult to estimate, but detailed cost-benefit
analyses have been established. The main issues for consideration are reduced
quality of life (and burden on social services), osteoporosis (and potential
increased fracture rate) and increased cardiac risk (potential increase risk
of cardiac death).
The effect of somatotrophin replacement on long term cardiac
morbidity will only emerge from very long term surveillanceof treated
patientsand multinational databases have been established for this
purpose (19). Studies have shown somatotrophin supplementation to reduce
total cholesterol by about 15%. Studies with other drug therapies estimate
that reducing total cholesterol by 10% causes a 30% reduction in the incidence
of symptomatic coronary heart disease. Cardiac disease carries the cost of
acute and long term treatments.
Studies show that a 4-year course of somatotrophin can increase
bone density by approximately 12%. It seems reasonable to assume that this
would reduce fracture rates and the costs of acute and long-term management.
Conclusive evidence will emerge from long term clinical surveillance.
Studies in Sweden show that patients with somatotrophin deficiency
are more likely to unemployed, retire early, suffer from depression, require
disablement pension and have a two-fold higher utilisation of health-care
resources. The costs to social services and the health service should therefore
be included.
Shared Care
Suggested provisional responsibilities under shared care arrangements
are as follows:
The hospital will:
Carry out the initial assessment and baseline measurements.
See the patient every 2 weeks during the titration phase and
subsequently 3-6 monthly.
The following tests are carried out:
Baseline pituitary imaging (preferably with MRI) and then
at 6 monthly intervals for first year. Annual imaging thereafter in patients
with known residual pituitary tumour.
Regular serum IGF-1 during titration stage.
Waist:hip ratio.
Blood pressure.
AGHDA questionnaire - 3 monthly.
Bone density at 0 and then each 12 months.
Thyroid function and serum biochemistry - baseline and then
6 monthly.
Glucose and HbAlc baseline and then 6 monthly.
Weight and body mass index.
Produce a report at 6 months (or 2 years) as agreed to compare
response to baseline measurements
and enable a decision on long-term replacement to be made.
Educate the patient on somatotrophin and its correct administration.
Advise the patient and GP of any dose adjustments.
Provide a suitable injection device and an initial supply of
a cartridge.
The General Practitioner will:
Monitor the patient every 3 months initially and then 6 monthly
when stable and carry out the following, tests:
Weight.
Blood pressure.
Glucose and HbAlc (6 monthly)
Monitor the patient for side effects. Prescribe the somatotrophin
on the advice from the hospital.
The relative roles of the hospital specialist and general practitioner
may vary depending on geographical considerations, patient convenience and
local contracting.
John Monson and Stephen Nussey
Consultant Endocrinologists
This document has been approved by the Clinical Committee of
the Society for Endocrinology, 22 Apex Court, Woodlands,
Bradley Stoke, Bristol BS32 4JT. Tel: +44 (0)1454 642200; Fax: +44
(0)1454 642222;.
References
Rosén T, Bengtsson B-Å. Premature mortality due to cardiovascular
disease in hypopituitarism. Lancet. 1990, 336, 285-8.
Littley MD, Shalet SM, Beardwell CG, Ahmed SR, Applegate
G, Sutton ML. Hypopituitarism following external radiotherapy for pituitary
tumours in adults. Quarterly Journal of Medicine. 1988 262 145-160.
Mårdh G, Landin K, Borg G, Jonsson B, Lindeberg A, on behalf
of the investigators. Growth hormone replacement therapy in adult hypopituitary
patients with growth hormone deficiency: Combined data from 12 European
placebo-controlled clinical trials. Endocrinol. Metab. 1994, l(SupplA),
43-9.
Fowelin J, Attrall S, Lager I, Bengtsson B-Å. Effects of
treatment with recombinant human growth hormone on insulin sensitivity
and glucose metabolism in adults with growth hormone deficiency. Metabolism.
1993, 42, 1443-7.
Johansson J-Q, Landin K, Tengboru L, Rosén T, Bengtsson
B-Å. High fibrinogen and plasminogen activator inhibitor activity in growth
hormone deficient adults. Arterioscler, Thromb. 1994 14 434-7.
Markussis V, Beshyah SA, Fischer C, Sharp P, Nicolaides
AN, Johnson DG. Detection of premature atherosclerosis by high resolution
ultrasonography in symptom-free hypopituitary adults. Lancet. 1992, 340,
1188-92.
Capaldo B, Patti L, Oliverio U, Longobardi S, Pardo F, Vitali
F, Fazio S, di Reller F, Bindi B, Lombardi G, Sacca L. Increased arterial
intimi-media thickness in childhood onset growth hormone deficiency . J.
Clin. Endocrinol. Metab. 1997, 82, 1378-81.
Hoffman DM, OSullivan AJ, Baxter RC, Ho KY. Diagnosis
of growth hormone deficiency in adults. Lancet. 1994, 343,
1064-8.
Granada ML, Janmarti A, Lucas et al. Assay dependent results
of immunoassayable spontaneous 24-hour growth hormone secretion in short
children. Acta Paediatri. Scand. 1990 (suppl 370), 63-70.
Rahim A, Toogood AA, Shalet SM. The assessment of growth
hormone status in normal young adult males using a variety of provocative
agents. Clinical Endocrinologv. 1996, 45. 557-62.
De Boer H, Blok G-J, Van der Keen EA. Clinical aspects of
growth hormone deficiency in adults. Endocrine Reviews. 1995, 16,
63-86.
Bengtsson BÅ, Eden S, Lönn L, Kvist H, Stockland A, Lindstedt
G et al. Treatment of adults with growth hormone deficiency with recombinant
human growth hormone. J. Clin. Endocrinol. Metab. 1993,
76, 309-17.
Weaver JU, Monson JP, Noonan K, Price C, Edwards A, Evans
KA, James I, Cunningham J. The effects of low dose recombinant human growth
hormone replacement on indices of bone remodelling and bone mineral density
in hypopituitary growth hormone deficient adults. Endocrinol. Metab.
1996 3 55-61.
Johansson G, Rosén T, Bosaeus I, Sjoström L, Bengtsson B-Å.
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. 1996, 81, 2865-73.
Weaver JU, Monson JP, Noonan K, John WG, Edwards A, Evans
KA, Cunningham JC. The effect of low dose recombinant human growth hormone
replacement on regional fat distribution and cardiovascular risk factors
in hypopituitary adults. J. Clin. Endocrinol. Metab. 1995 80 153-9.
Olivecrona H, Ericsson S, Berglund L, Angelin B. Increased
concentrations of serum lipoprotein (a) in response to growth hormone treatment. Brit.
Med. J. 1993, 306, 1726-7.
Amato G, Carella C, Fazio S, La Montagne G, Cittadini A,
Sabatini D. et al. Body composition, bone metabolism and heart structure
and function in growth hormone (GH) deficient adults before and after GH
replacement therapy at low doses. J. Clin. Endocrinol. Metab. 1993 77 1671-6.
Abs R, Bengtsson B-Å, Hemberg-Stahl E, Monson JP, Tauber
JP, Wilton P, Wuster C on behalf of the KIMS Study Group. GH replacement
in 1034 GH deficient adults: demographic and clinical characteristics,
dosing and safety. Annals d'Endocrinologie. 1997, 58 (Suppl
1), p15.