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Adult Growth Hormone Replacement...

From http://www.endocrinology.org/sfe/gh.htm

Introduction

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

Clinical features

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:

  1. 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.
  2. 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)
  3. 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.
  4. 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).
  5. 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

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:

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:

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

  1. Rosén T, Bengtsson B-Å. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet. 1990, 336, 285-8.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Bülow B, Hacrmar L, Mikoczy Z, Nordström CH, Erfurth EM. Increased cerebrovascular mortality in patient with hypopituitarism. Clinical Endocrinology. 1997, 46, 75-81.
  9. Hoffman DM, O’Sullivan AJ, Baxter RC, Ho KY. Diagnosis of growth hormone deficiency in adults. Lancet. 1994, 343, 1064-8.
  10. 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.
  11. 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.
  12. De Boer H, Blok G-J, Van der Keen EA. Clinical aspects of growth hormone deficiency in adults. Endocrine Reviews. 1995, 16, 63-86.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.

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