Download Management of growth hormone deficiency in adults

DRUG REVIEW n
Management of growth hormone
deficiency in adults
Successful management of adults with
growth hormone deficiency requires an
effective shared care partnership between
primary and secondary care. In this article, Dr
Bujanova and Professor Cummings discuss
the signs and symptoms of growth hormone
deficiency in adults, the range of growth
hormone replacement products available
and the GP’s role in management.
SPL
Jana Bujanova and Michael H Cummings
A
dult growth hormone deficiency (AGHD) is a recognised clinical syndrome associated with debilitating symptoms affecting quality of life, psychosocial functioning and a number of
metabolic abnormalities, and which can improve with growth
hormone (GH) replacement therapy.1 Recombinant human GH
was first licensed in the UK in 1999 and its use in adults and
children with GH deficiency was formalised and standardised
by NICE in 2003 and 2010 respectively.2,3
The estimated prevalence of AGHD in the UK is approximately 1 in 10 000 (a total of approximately 6380 patients). If
childhood-onset GH deficiency is added to this number (prevalence 1 in 10 000 to 1 in 3500) it is highly probable that every
GP practice will come across a patient who has been evaluated
for or is currently treated for GH deficiency. Therefore, it is useful
for all clinicians involved in GH prescribing to understand the
rationale behind treatment initiation, practical aspects of GH
therapy, and the expected benefits and side-effects associated
with treatment.
Causes of growth hormone deficiency
Growth hormone is produced by somatotroph cells in the anterior pituitary gland. Any pathological process affecting the pituitary gland or hypothalamus can be a cause of AGHD. In adults
the most common cause (76 per cent) of GH deficiency is a pituitary tumour or a consequence of its treatment such as surgery
and/or radiotherapy 4 (see Figure 1). Rarer causes include
inflammatory diseases affecting the pituitary gland such as sarcoidosis, haemorrhage into the pituitary gland or previous traumatic head injury. Patients with an organic pituitary problem
are likely to have multiple pituitary hormone deficiencies and
require other hormone replacement therapies such as hydrocortisone, levothyroxine, testosterone or oestrogen preparations. Childhood-onset GH deficiency may be idiopathic and
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n DRUG REVIEW l Growth hormone deficiency
Symptoms
Fatigue, reduced vitality and energy
Depressed mood and emotional lability
Greater sense of social isolation
Difficulties with sexual relationships
Signs
Reduced lean body mass
Increased abdominal adiposity
Reduced muscle strength and exercise capacity
Thin and dry skin due to reduced sweating
Reduced bone mineral density
Cool peripheries and poor venous access
Table 1. The clinical features of growth hormone deficiency in adults
Figure 1. MRI of patient with pituitary macroadenoma and
hypopituitarism
isolated, and it continues to adulthood in approximately onethird of affected children.
Symptom and signs of GH deficiency
The most recognised sign of GH deficiency in childhood is a
short stature whereas in adults the main manifestations are
less specific (see Table 1). Patients who develop GH deficiency
in adulthood are psychologically less healthy and score less on
quality-of-life assessment questionnaires.5
Those with GH deficiency have a significantly increased risk
of cardiovascular disease and mortality.4,6 Data suggest that
GH deficiency in adulthood is associated with dyslipidaemia,7,8
insulin resistance,9 increased inflammatory markers,10 endothelial dysfunction,11 and higher coronary artery calcium score – a
marker of early atherosclerosis.12
There is substantial evidence that GH treatment in adults
with GH deficiency increases muscle mass, decreases body fat
and improves cardiac function. Studies investigating the effect
of GH treatment on body composition demonstrated a decrease
in central adiposity,13 an increase in lean body mass14 and an
increase in exercise capacity.15 GH increases total plasma volume and stimulates erythropoiesis, which may contribute to
increased exercise performance.16 Cardiac effects of GH include
an increase in left ventricular mass, wall thickness and stroke
volume due to the anabolic action of GH on cardiac muscle and
an increase in plasma volume.17 There is evidence that GH therapy reduces carotid intima-media thickness18 and has beneficial
effect on C-reactive protein – a marker of inflammation. 19
Reduction in low density lipoprotein cholesterol (LDL-C) and
apolipoprotein B (ApoB) has been demonstrated in some20 but
not all19 studies examining the impact of GH upon plasma lipid
profiles. Trials examining the effect of GH replacement have
demonstrated an improvement in psychosocial wellbeing and
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quality of life21 and a reduction in consumption of healthcare
resources.22
A summary of evidence by Monson suggests that GH does
not only provide short-term improvements in the above parameters but its effect is maintained with long-term administration.23 Mortality among recipients of GH replacement therapy
is similar to that of the general population, which suggests that
treatment may reduce mortality in the population with GH deficiency at risk of cardiovascular disease.24
In our clinical experience, the main benefits reported by
patients are changes in cognitive function and interaction and
an increase in energy levels. In some, this has had a profound
impact on their ability to keep their employment and to remain
economically active.
Susceptible patient groups
GH deficiency in adulthood should be suspected and tested for
in symptomatic patients with known hypothalamic or pituitary
disease and documented deficiency of other pituitary hormones. Testing should be considered in patients with history of
GH deficiency in childhood and in those with a history of traumatic brain injury where damage to the pituitary gland or pituitary stalk could have occurred.
An insulin tolerance test (ITT) is the gold standard diagnostic
tool for AGHD and utilises insulin-induced hypoglycaemia as a
powerful stimulant of GH release. Severe GH deficiency in adults
is defined as a peak concentration of <9mU per litre (<3ng per
ml) in response to insulin-induced hypoglycaemia.
NICE advocates recombinant human GH (somatropin) use
in carefully preselected patients who are most likely to benefit.2
Patients must fulfil all three of the following criteria:
• Severe growth hormone deficiency defined as GH of < 9mU
per litre (<3ng per ml) during an insulin tolerance test or a crossvalidated GH threshold in an equivalent test
• Perceived impairment of quality of life demonstrated by a
reported score of at least 11 in the disease-specific Quality of
Life assessment of growth hormone deficiency in adults (QoLAGHDA) questionnaire2
• Already receiving treatment for any other pituitary hormone
deficiencies as required.
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Growth hormone deficiency
l DRUG REVIEW n
GH prescribing
Typically, treatment of GH deficiency with recombinant human
GH should be part of a shared-care protocol between primary
and secondary care. Following assessment by and recommendation to commence GH replacement therapy by a consultant
endocrinologist with interest in AGHD, a shared-care agreement
to confirm local primary care ability to continue prescribing GH
must be obtained. Following confirmation of this arrangement,
patients are invited to attend a demonstration session run by
an endocrine specialist nurse, who is trained in management
of AGHD and is able to demonstrate the variety of GH products
available. Once patient choice is confirmed, typically a GH
starter pack including a three-month supply of GH is provided
by the pharmaceutical company.
Seven preparations of recombinant human GH are currently available in the UK.25 They come with a variety of delivery
devices and vary in price (see Table 2). The average annual
cost of therapy depends on the daily maintenance dose, which
is determined by age, weight, size of the patient and the concomitant use of oral oestrogen preparations, and is quoted to
be approximately £3350 per patient.2 There are no known differences in the efficacy of the various preparations and the
choice depends upon the individual area’s prescribing committee and negotiated discounts with pharmaceutical companies as well as patient’s choice of delivery device and local
experience.
Locally, we demonstrate all available GH products and
devices to patients. These vary in price but also in the complexity of assembly and administration. We firmly believe that the
patient’s involvement in choosing the right delivery device for
their circumstances is extremely important for subsequent compliance with treatment. Patient education, initiation of GH therapy, titration of the dose and monitoring of the patient’s
response and GH side-effects is commonly provided by the
endocrine specialist nurse. In areas where this arrangement is
not available, all GH pharmaceutical companies offer homecare
support. This involves initiation of GH therapy in the patient’s
home environment by the company’s home support nurse, but
does not include IGF-1 monitoring or dose titration.
In order to minimise side-effects, GH is initiated at a low
dose and gradually titrated. NICE recommends that the initial
starting dosage is 0.2–0.3mg (0.6–0.9 units) daily. For the first
two to three months, the dosage is adjusted after monthly
assessments of insulin-like growth factor 1 (IGF-1) until the
maintenance dosage is achieved. The usual maintenance
dosage is around 0.4mg (1.2 units) daily and the goal of maintenance therapy is to maintain serum IGF-1 levels within the
middle of the age-adjusted normal range. After nine months of
treatment, the QoL-AGHDA questionnaire is re-examined and
improvement of at least seven points on this scale is required
for GH continuation (see Figure 2).
Side-effects
The most commonly reported side-effect of GH therapy is fluid
retention resulting in mild peripheral oedema. Other side-effects
include arthralgia, carpal tunnel syndrome, paraesthesia and
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Diagnosis of GH deficiency and presence of NICE
criteria for GH therapy
Shared-care agreement with primary care
Demonstration of available devices to patients
Teaching the chosen device and injection technique
Starting GH dosage 0.2–0.3mg (0.6–0.9 units) daily sc
Month 1–3 (titration period)
Monthly IGF-1 levels and dose titration. Likely to
achieve maintenance dose by end of month 3
Month 3–9
Therapeutic trial with maintenance dose
Month 9
Assessment of response + Qol-AGHDA scoring
QoL-AGHDA score
improvement ≥7 and patient
wishing to continue with
therapy
QoL-AGHDA score
improvement <7
Discontinuation of GH therapy
Ongoing GH therapy
Figure 2. Growth hormone (GH) therapy initiation and titration. QoL-AGHDA =
Quality of Life assessment of growth hormone deficiency in adults
worsening glucose tolerance. The most serious side-effect is
benign intracranial hypertension presenting with symptoms of
papilloedema, headaches and sickness but this is very rare.
Adverse events can be prevented by maintaining IGF-1 within
the middle of the age-adjusted reference range.
Active malignancy is considered to be a contraindication to
GH replacement therapy due to the possibility that the GH can
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n DRUG REVIEW l Growth hormone deficiency
stimulate tumour growth, but the exposure to GH therapy does
not seem to be associated with pituitary tumour growth or recurrence.26
The GP’s role in management
The GP’s involvement in management of patients with GH deficiency is crucial for a successful shared care partnership, as
described above. Although GH therapy is costly, patients are
carefully preselected and the adult doses of GH are significantly
lower than those required in childhood and adolescence.
Awareness of potential GH side-effects by GPs and their early
identification can ensure that IGF-1 levels are reviewed early and
dose is down-titrated to minimise adverse effects. GPs will often
be in the front line when diagnosing conditions in which GH is
contraindicated such as malignancy. They are crucial in the identification of vulnerable patient groups at risk of hypopituitarism
who would not routinely be known to endocrinologists, such as
childhood cancer survivors with previous cranial or total body
irradiation or those with a history of traumatic brain injury.
References
1. Carroll PV, et al. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab
1998;83:382–395.
2. NICE. Human growth hormone (somatropin) in adults with growth
hormone deficiency. NICE TA64. August 2003.
3. NICE. Human growth hormone (somatropin) for the treatment of
growth hormone failure in children. NICE TA188. May 2010.
Brand name
Available preparations
Device
Omnitrope
5mg (15 unit) cartridge
10mg (30 unit) cartridge
Omnitrope Pen 5
Omnitrope Pen 10
Genotropin
5.3mg (16 unit) cartridge
12mg (36 unit) cartridge
5.3mg (16 unit) prefilled pen
12mg (36 unit) prefilled pen
0.2mg (0.6 unit) syringe (with diluent)
0.4mg (1.2 unit) syringe (with diluent)
0.6mg (1.8 unit) syringe (with diluent)
0.8mg (2.4 unit) syringe (with diluent)
1.0mg (3 unit) syringe (with diluent)
1.2mg (3.6 unit) syringe (with diluent)
1.4mg (4.2 unit) syringe (with diluent)
1.6mg (4.8 unit) syringe (with diluent)
1.8mg (5.4 unit) syringe (with diluent)
2.0mg (6 unit) syringe (with diluent)
Genotropin Pen 5
Genotropin Pen 12
GoQuick prefilled pen
GoQuick prefilled pen
MiniQuick single dose syringe
MiniQuick single dose syringe
MiniQuick single dose syringe
MiniQuick single dose syringe
MiniQuick single dose syringe
MiniQuick single dose syringe
MiniQuick single dose syringe
MiniQuick single dose syringe
MiniQuick single dose syringe
MiniQuick single dose syringe
Humatrope
6mg (18 unit) cartridge (with diluent)
12mg (36 unit) cartridge (with diluent)
24mg (72 unit) cartridge (with diluent)
HumatroPen 6 mg
HumatroPen 12 mg
HumatroPen 24 mg
Zomacton
4mg (12 unit) vial (with diluent)
10mg (30 unit) vial (with diluent)
For use with ZomaJet 2 Vision device
For use with ZomaJet Vision X device
NutropinAq
10mg (30 unit) cartridge
NutropinAq Pen
Norditropin
SimpleXx cartridge 5mg (15 unit)
SimpleXx cartridge 10mg (30 unit)
SimpleXx cartridge 15mg (45 unit)
NordiFlex prefilled pen 15mg (45 unit)
NordiPen
NordiPen
NordiPen
NordiFlex prefilled pen
Saizen
6mg (18 unit) cartridge
12mg (36 unit) cartridge
20mg (60 units) cartridge
8mg (24 unit) vial (in click.easy device with diluent)
For use with cool.click or easypod autoinjector device
For use with cool.click or easypod autoinjector device
For use with cool.click or easypod autoinjector device
For use with one.click, cool.click or easypod
autoinjector devices
Table 2. Recombinant human growth hormone (somatropin) products available in the UK (in order of cost)25
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Growth hormone deficiency
4. Bates AS, et al. The effect of hypopituitarism on life expectancy. J Clin
Endocrinol Metab 1996;81:1169–72.
5. Hazem A, et al. Body composition and quality of life in adults treated
with GH therapy: a systematic review and meta-analysis. Eur J Endocrinol 2012;166:13–20.
6. Rosèn T, Bengtsson BA. Premature mortality due to cardiovascular
disease in hypopituitarism. Lancet 1990;336:285–8.
7. De Boer H, et al. Serum lipid levels in growth hormone-deficient men.
Metab Clin Exp 1994;43:199–203.
8. Cuneo RC, et al. Growth hormone treatment improves serum lipids
and lipoproteins in adults with growth hormone deficiency. Metabol Clin
Exp 1993;42:1519–23.
9. Johansson JO, et al. Growth hormone-deficient adults are insulin resistant. Metab Clin Exp 1995;44:1126–29.
10. Sesmilo G, et al. Inflammatory cardiovascular risk markers in women
with hypopituitarism. J Clin Endocrinol Metab 2001;86:5774–81.
11. Elhadd TA, et al. Biochemical and biophysical markers of endothelial
dysfunction in adults with hypopituitarism and severe GH deficiency. J
Clin Endocrinol Metab 2001;86:4223–32.
12. Cannavò S, et al. High prevalence of coronary calcifications and increased risk for coronary heart disease in adults with growth hormone
deficiency. J Endocrinol Invest 2011;34:32–7.
13. Bengtsson BA, et al. Treatment of adults with growth hormone (GH)
deficiency with recombinant human GH. J Clin Endocrinol Metab
1993;76:309–17.
14. Baum HB, et al. Effects of physiologic growth hormone therapy on
bone density and body composition in patients with adult-onset of
growth hormone deficiency. A randomised, placebo controlled trial. Ann
Intern Med 1996;125:883–90.
15. Widdowson WM, Gibney J. The effect of growth hormone replacement on exercise capacity in patients with GH deficiency: a meta-analysis. J Clin Endocrinol Metab 2008;93:4413–7.
17. Maison P, Chanson P. Cardiac effects of growth hormone in adults
with growth hormone deficiency: a meta-analysis. Circulation
2003;108:2648–52.
18. Colao A, et al. Growth hormone treatment on atherosclerosis: results
of a 5-year open prospective, controlled study in male patients with severe growth hormone deficiency. J Clin Endocrinol Metab 2008
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;93:3416–24.
19. Beauregard C, et al. Growth hormone decreases visceral fat and improves cardiovascular risk markers in women with hypopituitarism: a
randomised, placebo controlled study. J Clin Endocrinol Metab
2008;93:2063–71.
20. Christ ER, et al. Effects of growth hormone (GH) replacement therapy on very low density lipoprotein apolipoprotein B100 kinetics in patients with adult GH deficiency: a stable isotope study. J Clin Endocrinol
Metab 1999;84:307–16.
21. McGauley GA. Quality of life assessment before and after growth
hormone treatment in adults with growth hormone deficiency. Acta Pediatr Scand 1989;356(Suppl):70–4.
22. Hernberg-Stahl E, et al. Healthcare consumption decreases in parallel with improvements in quality of life during GH replacement in hypopituitary adults with GH deficiency. J Clin Endocrinol Metab
2001;86:5277–81.
23. Monson JP. Long-term experience with GH replacement therapy: efficacy and safety. Eur J Endocrinol 2003;148:S9–14.
24. Bengtsson BA, et al. Growth hormone replacement therapy is not
associated with any increase in mortality. KIMS Study Group. J Clin Endocrinol Metab 1999;84:4291–2.
25. BNF Online. October 2015 [last accessed online 2 November
2015].
26. Frajese G, et al. Hypothalamo-pituitary surveillance imaging in hypopituitary patients receiving long-term GH replacement therapy. J Clin
Endocrinol Metab 2001;86:5172–5.
Declaration of interests
None to declare.
Dr Bujanova is a specialist registrar and a clinical research
fellow in endocrinology and diabetes at Queen Alexandra
Hospital, Portsmouth and Professor Cummings is a consultant in endocrinology and diabetes at Queen Alexandra
Hospital, Portsmouth and honorary professor with the
University of Portsmouth
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