Suffolk & Therapeutics Committee

Shared Care Guidelines for Growth Replacement in Adult Growth Hormone Deficiency

What is a shared care document?

Suffolk D&T operates a traffic light system in an attempt to clarify prescribing responsibility and improve consistency across Suffolk: Double Red – Prescribing within hospital or general practice would not be supported. Red – Hospital only Amber – Hospital initiated but suitable for GP prescribing if a suitable shared care document is in place. Green – Hospital initiated; GP prescribing Double Green – GP prescribing

The basic principles of a shared care arrangement are: 1) The shared care document will include a clear statement of the hospital specialist/GPs responsibilities 2) Shared care documents must provide sufficient information such that after patient stabilisation under hospital supervision, prescribing responsibility could safely be transferred to primary care 3) Both hospital specialist and general practitioner have a duty of care for the overall management of the patient 4) Patient convenience may be a major factor for GPs taking on prescribing responsibility and not the cost of the therapy 5) The onus is on the hospital specialist to liase with the GP, and if the GP does not wish to undertake the clinical and legal responsibility for the drug he does not have to do so. Responsibility to prescribe will therefore remain with the hospital 6) Agreement to accept prescribing responsibility should be obtained from the GP before the patient is informed For more details please refer to the traffic light document on the Suffolk Public Health website www.sphn.nhs.uk

Document prepared on behalf of the Departments of Diabetes and Endocrinology at The Ipswich Hospital, West Suffolk Hospital. Contact details as follows: Drs C Parkinson, G Rayman and PD Fowler Department of Diabetes and Endocrinology The Ipswich Hospital NHS Trust Heath Road Ipswich IP5 5PD Tel 01473 704181 (Sec to Dr C Parkinson)

Drs Clark, Majeed and Wijenaike West Suffolk Hospitals NHS Trust Hardwick Lane, Bury St Edmunds Suffolk, IP33 1QZ Tel 01284 713000 This is an NHS Suffolk document that has been adopted by the WSCCG. Please note that Dr Huston at James Paget Hospital was consulted regarding his involvement in the development of this shared care protocol. However, the majority of patients he considers for this treatment reside in catchment areas served by the Norfolk and Norwich Hospital. The small number of patients residing within East Suffolk will therefore be referred to The Ipswich Hospital Trust for investigation and consideration of treatment.

Date received by Suffolk D&T and approved by the Local Medical Committee March 2005 Review Date March 2006 Persons consulted in the development of this document: Dr PD Fowler, Dr C Parkinson, Dr G Rayman, Dr J Clark, Dr J Majeed, Dr N Wijenaike and Dr N Huston.

Background to shared care document: Growth Hormone Deficiency (GHD) has long been recognised as a condition in children. It is only since the late 1980s that it has been realised that adults are also physically and psychologically disadvantaged as a result of GHD and can benefit from replacement therapy1.

Over the last decade adult patients with GHD have been treated in clinical trials with replacement biosynthetic growth hormone (GH). GH treatment has shown positive benefits for both short-term and long-term health. Replacement therapy has also improved quality of life (QOL) in selected patients, bringing energy and vigour back to these patients, and enabling them to lead a more normal life2.

In the future an increased awareness of this endocrine deficiency and consequent increase in diagnosis will lead to a growth in this treatment area. With an estimated incidence of 1:10,000, GHD in adults is a condition which general practitioners will now occasionally come into contact with in the course of their work.

The Suffolk D&T Committee has not previously reviewed GH therapy in adults.

NICE technology appraisal guidance number 64 (www.nice.org.uk/Docref.asp?d=83429) discusses GH therapy in patients with GHD. Section 1.1 of this guidance states “Recombinant human growth hormone (somatropin) treatment is recommended for the treatment of adults with GH deficiency only if they fulfil 3 selection criteria (see later)”. It is suggested in this appraisal that prescribing maintenance therapy may take place in primary care under an approved shared care guideline. The role of growth hormone replacement in the treatment of adult growth hormone deficiency

Growth hormone is released from the with secretion rates peaking during the night. Although production declines after the growth spurt of adolescence, GH continues to be produced and to play an important metabolic role throughout life.

Key Effects of GH – Important role in the regulation of and body composition in adults. Widespread effects include stimulation of cartilage and growth, lypolysis resulting in reduced body fat, anti-naturiuretic action leading to increased extra-cellular water, anabolic action leading to increased cell mass and direct / indirect effects on mental function / QOL.

Causes of GHD – Adult GHD is a relatively rare condition, affecting approximately 1 in 10,000 of the total population3. The majority of patients have pituitary or peri-pituitary tumours, or have been treated for such tumours in the past. GHD is a side effect of cranial radiotherapy for other cancer and approximately one third of children with idiopathic GHD will remain GH deficient as adults.

Signs and symptoms of GHD – The most obvious reduction is in physical well- being and the most prominent of these indicators are low energy levels, social isolation, lack of positive well-being, depressed mood and increased anxiety. While QOL indicators are difficult to quantify, the symptom severity of each patient should be assessed together with the overall degree of dysfunction. Evidence exists for the benefits of GH replacement on QOL over baseline assessments.

In addition there is growing evidence to suggest that some of the changes associated with adult GHD may be responsible for increased morbidity and mortality from cardiovascular disease which occurs with a higher frequency in these patients.

Physical signs of GHD include increased body fat, reduced muscle mass, reduced bone mineral density, reduced exercise capacity, poor physical performance, raised serum cholesterol, reduced cardiac muscle mass and impaired cardiac function.

Benefits of GH replacement – Many of the psychological and physical features of GHD are improved by replacement. Clinical trials have shown improvements as follows4, 6, 7. • Improved lipid profile • Cardiac structure and function improved • Increased exercise capacity • Improved bone mineral density • Normalisation in body cell mass and extra-cellular water • Reduction in body fact (particularly intra-abdominal fat) • Improved renal function • Improved well-being and QOL • Increased vitality

While GH replacement improves a range of cardiovascular markers, further studies are required to confirm the effects of therapy on cardiovascular related mortality and morbidity.

Patient Selection for GH replacement – To be carried out by a hospital endocrinology specialist. • Patients seen at the James Paget Hospital who reside in East Suffolk may be referred to the Ipswich Hospital for consideration of GH replacement therapy. • The condition is diagnosed at hospital level by initial clinical suspicion in patients likely to have GHD. Patients under clinical suspicion will include: o Patients with known or suspected hypothalamic or pituitary disease o Patients who have received cranial irradiation o Patients with a deficiency of one or more other pituitary o Patients who have undergone pituitary surgery o Adults who have received GH in childhood for GHD • An accepted definition of severe adult GHD is a peak GH response below 3ng/ml or 9mU/L during a provocative test. • The tolerance test is the gold standard provocative test used in the diagnosis of adult GHD. The glucagon stimulation and arginine stimulation tests are alternatives. • Tests should be considered only after stabilisation of treatment for other pituitary deficiencies and at least one month after pituitary surgery. Childhood treatment with GH should be interrupted for an appropriate period (usually 3 months) before retesting GH status. • In accordance with the NICE technology appraisal guidance (number 64) treatment will only be recommended if patients fulfil all three of the following criteria: o They have severe GHD as a peak GH response less than 9mU/L (3ng/ml) during an insulin tolerance test or a cross- validated GH threshold in an equivalent test. o They have a perceived impairment of QOL, as demonstrated by a reported score of at least 11 in the disease-specific ‘Quality of life assessment of GHD in adults’ (QOL-AGHDA) questionnaire (copy included with this document) o They are already receiving treatment for any other pituitary hormone deficiencies as required

Hospital Specialist Responsibilities For the purposes of this document a hospital endocrinology specialist may refer to either a consultant physician, GP with a specialist interest in endocrinology and Specialist Registrar or Endocrine Nurse Practitioner working under the supervision of a clinician • Selection of patients for GH therapy, including discussion with the patient of the dosage and method of administration, side effect profile, special precautions. • The hospital specialist will also provide the patient with a drug information sheet (similar to that included in this document – to be formalised). • Baseline clinical assessment – to include: current medical history, full history of hypothalamic-pituitary disease, surgical and radiological history, number of pituitary hormone deficiencies, current replacement regimen, previous GH treatment, QOL assessment using QOL- AGHDA. • Baseline medical / biochemical assessment – to include: height, weight, BMI, pressure, HBA1c, lipid profile, insulin like growth factor 1 (IGF-I), recent pituitary imaging, visual field assessment where relevant. • The hospital specialist will be responsible for writing prescriptions for GH first nine months of treatment. This initial assessment period will allow for adjustment and stabilisation of the dose of GH. o Dose – GH is started at low dose (0.15-0.3mg/day (0.45- 0.9IU/day)) and is gradually increased. Sensitivity varies with age, weight and gender. The dose will be calculated by the hospital clinician in accordance with data sheet recommendations (usual maintenance dose up to 1mg/day (3IU/day)) o Monitoring the dose – the recognised technique is measurement of IGF-I which should increase with therapy and should be maintained in the upper half of the normal range during therapy. IGF-I will be checked at 1-2 monthly intervals during the first 3 months of treatment until the optimum maintenance dose is reached o This will be followed by a 6 month therapeutic trial period o Delivery – GH is self-administered by subcutaneous injection in the evening before bedtime. Training facilities for patients to learn to self-inject are already established. Where patients/carers cannot be taught to self-inject or become unable to do so it will be the hospital specialists’ responsibility to make alternative arrangements. There may not be the resources within GP practices to provide an administration service for such patients. • After completion of the 6 month therapeutic trial period patients will be re-assessed including QOL status. GH treatment will be discontinued where a QOL improvement of less than 7 points has been observed. Those with QOL improvements of 7 or more points will be eligible to continue therapy and the hospital specialist will write to the GP inviting him/her to partake in a shared care agreement and detailing the patients continuing management strategy. • If the GP is not in agreement, prescribing responsibility will remain with the hospital specialist. • After hand over to the GP, the hospital specialist will be responsible for:  Annual medical assessment comprising:  Height, weight and BMI  Blood pressure  HABA1c  Lipid profile  Serum IGF-I  Pituitary imaging as appropriate  Visual field measurement where relevant  Assessment of QOL (QOL-AGHDA)  Monitoring of patients overall health and well-being  Adjustment of dose where appropriate  Discussion with patient regarding adverse effects  Monitoring self-administration and compliance

GP responsibilities • After nine months of treatment (with patient stabilised and free from any treatment-related adverse events) the patients GP will be asked to assume responsibility for prescribing GH and sent a treatment plan, including prescription details re: preparation used, administration device, dose and frequency of administration and quantity prescribed. • If in agreement the GP will be responsible for on going prescriptions of GH therapy and annual medical checks (to occur six months after each annual hospital visit) comprising:  Height, weight, BMI  Blood pressure  Monitoring of overall patient health and well-being  Observation and report of any unexpected side effects to the hospital clinician (severe headaches to be reported immediately)  Monitoring of self administration and compliance

Side effects Fluid retention is the most commonly reported ‘side effect’ of GH replacement. Fluid retention, with occasional mild ankle oedema is a part of normal GH action. This tends to decrease as therapy continues but may occasionally require a dose reduction9.

Carpal tunnel syndrome and headache have been among reported side effects and are usually mild and self-limiting but a reduction in GH dose may be required if they persist.

GH therapy has been shown to reduce insulin sensitivity in patients with GHD by antagonising the action of insulin – this could increase the risk of diabetes mellitus10.

A severe persistent headache should be reported to the endocrinology department.

There is no evidence to suggest that GH therapy in the doses used will increase the risk of abnormal or neoplastic growth, either a new growth or a resurgence of an old tumour.

See Summary of Product Characteristics for further details. Prescribing information for GH in adult GHD

Summary prescribing information for guidance only; please refer to the full SPC (available at www.medicines.org then emc(registration required)), local specialist or medicines information centre. The information is correct at the time of writing – April 04 – but maybe subject to change.

Recombinant Human Growth Hormone (Somatropin) –

Somatropin (INN) recombinant DNA-derived human growth hormone produced in E.coli.

Pharmacodynamic properties ATC code: H 01 A C 01

Somatropin is a potent metabolic hormone of importance for the metabolism of lipids, carbohydrates and proteins. In children with inadequate endogenous growth hormone, somatropin stimulates linear growth and increases growth rate. In adults, as well as in children, somatropin maintains a normal body composition by increasing nitrogen retention and stimulation of growth, and by mobilisation of body fat. Visceral adipose tissue is particularly responsive to somatropin. In addition to enhanced lipolysis, somatropin decreases the uptake of triglycerides into body fat stores. Serum concentrations of IGF-I (Insulin-like Growth Factor-I) and IGFBP3 (Insulin-like Growth Factor Binding Protein 3) are increased by somatropin. In addition, the following actions have been demonstrated:

Lipid metabolism: Somatropin induces hepatic LDL cholesterol receptors, and affects the profile of serum lipids and lipoproteins. In general, administration of somatropin to growth hormone deficient patients results in reductions in serum LDL and apolipoprotein B. A reduction in serum total cholesterol may also be observed.

Carbohydrate metabolism: Somatropin increases insulin, but fasting blood glucose is commonly unchanged. Children with hypopituitarism may experience fasting hypoglycaemia. This condition is reversed by somatropin.

Water and mineral metabolism: Growth hormone deficiency is associated with decreased plasma and extracellular volumes. Both are rapidly increased after treatment with somatropin. Somatropin induces the retention of sodium, potassium and phosphorus.

Bone metabolism: Somatropin stimulates the turnover of skeletal bone. Long term administration of somatropin to growth hormone deficient patients with osteopenia results in an increase in bone mineral content and density at weight bearing sites.

Physical capacity: Muscle strength and physical exercise capacity are improved after long term treatment with somatropin. Somatropin also increases cardiac output, but the mechanism has yet to be clarified. A decrease in peripheral vascular resistance may contribute to this effect.

Pharmacokinetic properties Absorption: The bioavailability of subcutaneously administered somatropin is approximately 80% in both healthy subjects and growth hormone deficient patients. A subcutaneous dose of 0.035 mg/kg of somatropin results in plasma Cmax and tmax values in the range of 13-35 ng/ml and 3-6 hours, respectively. Elimination: The mean terminal half life of somatropin after intravenous administration in growth hormone deficient adults is about 0.4 hours. However, after subcutaneous administration, half lives of 2-3 hours are achieved. The observed difference is likely due to slow absorption from the injection site following subcutaneous administration. Sub populations: The absolute bioavailability of somatropin seems to be similar in males and females following sc administration. Information about the pharmacokinetics of somatropin in geriatric and paediatric populations, in different races and in patients with renal, hepatic or cardiac insufficiency is either lacking or incomplete.

Preparations available – Genotropin®, Humatrope®, Norditropin®, Saizen® and Zomacton®

Licensed indications – Replacement therapy in adults with pronounced growth hormone deficiency. Patients with severe growth hormone deficiency in adulthood are defined as patients with known hypothalamic pituitary pathology and at least one known deficiency of a pituitary hormone not being prolactin. These patients should undergo a single dynamic test in order to diagnose or exclude a growth hormone deficiency. In patients with childhood onset isolated GH deficiency (no evidence of hypothalamic-pituitary disease or cranial irradiation), two dynamic tests should be recommended, except for those having low IGF-I concentrations (< 2 SDS (Standard Deviation Scores)) who may be considered for one test.

Recommended dosage and administration The dosage and administration schedule should be individualised. The injection should be given subcutaneously and the site varied to prevent lipoatrophy. Therapy should start with a low dose, 0.15 - 0.3 mg per day. The dose should be gradually increased according to individual patient requirements as determined by the IGF-I concentration. Treatment goal should be insulin-like growth factor (IGF-I) concentrations within 2 SDS from the age corrected mean. Patients with normal IGF-I concentrations at the start of the treatment should be administered growth hormone up to an IGF-I level into upper range of normal, not exceeding the 2 SDS. Clinical response and side effects may also be used as guidance for dose titration. The daily maintenance dose seldom exceeds 1.0 mg per day. Women may require higher doses than men, with men showing an increasing IGF-I sensitivity over time. This means that there is a risk that women, especially those on oral oestrogen replacement are under-treated while men are over- treated. The accuracy of the growth hormone dose should therefore be controlled every 6 months. As normal physiological growth hormone production decreases with age, dose requirements may be reduced. The minimum effective dose should be used.

Contra-indications – Somatropin should not be used when there is any evidence of tumour activity and anti-tumour therapy must be completed prior to starting therapy. Patients with acute critical illness suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions should not be treated with somatropin.

Cautions – Diagnosis and therapy with somatropin should be initiated and monitored by physicians who are appropriately qualified and experienced in the diagnosis and management of patients with the therapeutic indication of use. Somatropin may induce a state of insulin resistance and, in some patients, hyperglycaemia. Therefore, patients should be observed for evidence of glucose intolerance. In rare cases the diagnostic criteria for diabetes mellitus type II may be fulfilled as a result of the somatropin therapy, but risk factors such as obesity, family history, steroid treatment, or pre-existing impaired glucose tolerance have been present in most cases where this has occurred. In patients with an already manifest diabetes mellitus, the anti-diabetic therapy might require adjustment when somatropin is instituted.

During treatment with somatropin, an enhanced T4 to T3 conversion has been found which may result in a reduction in serum T4 and an increase in serum T3 concentrations. In general, the peripheral hormone levels have remained within the reference ranges for healthy subjects. The effects of somatropin on thyroid hormone levels may be of clinical relevance in patients with central sub clinical hypothyroidism in whom hypothyroidism theoretically may develop. Conversely, in patients receiving replacement therapy with thyroxine, mild hyperthyroidism may occur. It is, therefore, particularly advisable to test thyroid function after starting treatment with somatropin and after dose adjustments.

In growth hormone deficiency secondary to treatment of malignant disease, it is recommended to pay attention to signs of relapse of the malignancy.

In case of severe or recurrent headache, visual problems, nausea and/or vomiting, a funduscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and, if appropriate, the growth hormone treatment should be discontinued. At present there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.

Experience in patients above 60 years is limited.

Experience with prolonged treatment in adults is limited.

The effects of Genotropin on recovery were studied in two placebo controlled trials involving 522 critically ill adult patients suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma or acute respiratory failure. Mortality was higher in patients treated with 5.3 or 8 mg Genotropin daily compared to patients receiving placebo, 42% vs. 19%. Based on this information, these types of patients should not be treated with somatropin. As there is no information available on the safety of growth hormone substitution therapy in acutely critically ill patients, the benefits of continued treatment in this situation should be weighed against the potential risks involved. In all patients developing other or similar acute critical illness, the possible benefit of treatment with somatropin must be weighed against the potential risk involved.

Drug interactions – Data from an interaction study performed in growth hormone deficient adults suggests that somatropin administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by cytochrome P450 3A4 (e.g. sex steroids, , and cyclosporin) may be especially increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.

Pregnancy and lactation – No clinical experience of use in pregnant women is available. Animal experimental data are incomplete. Treatment with Genotropin should be interrupted if pregnancy occurs. During normal pregnancy, levels of pituitary growth hormone fall markedly after 20 gestation weeks being replaced almost entirely by placental growth hormone by 30 weeks. In view of this, it is unlikely that continued replacement therapy with somatropin would be necessary in growth hormone deficient women in the third trimester of pregnancy. It is not known if somatropin is excreted into breast milk, but absorption of intact protein from the of the infant is extremely unlikely.

Effects on ability to drive or use machines No effects on the ability to drive and use machines have been observed.

Adverse effects Patients with growth hormone deficiency are characterised by extracellular volume deficit. When treatment with somatropin is started, this deficit is rapidly corrected. In adult patients, adverse effects related to fluid retention such as peripheral oedema, stiffness in the extremities, arthralgia, myalgia and paraesthesia are common. In general, these adverse effects are mild to moderate, arise within the first months of treatment and subside spontaneously or with dose reduction.

The incidence of these adverse effects is related to the administered dose, the age of patients and possibly inversely related to the age of patients at the onset of growth hormone deficiency. In children, such adverse effects are uncommon.

Transient local skin reactions at the injection site in children are common.

Rare cases of diabetes mellitus type II have been reported.

Rare cases of benign intracranial hypertension have been reported.

Carpal tunnel syndrome is an uncommon event among adults.

Somatropin has given rise to the formation of antibodies in approximately 1% of patients. The binding capacity of these antibodies has been low and no clinical changes have been associated with their formation.

Somatropin has been reported to reduce serum cortisol levels, possibly by affecting carrier proteins or by increased hepatic clearance. The clinical relevance of these findings may be limited. Nevertheless, replacement therapy should be optimised before initiation of Genotropin therapy.

Very rare cases of leukaemia have been reported in growth hormone deficient children treated with somatropin, but the incidence appears to be similar to that in children without growth hormone deficiency.

Overdose No case of overdose or intoxication has been reported.

Acute over dosage could lead initially to hypoglycaemia and subsequently to hyperglycaemia. Long term over dosage could result in signs and symptoms consistent with the known effects of human growth hormone excess.

Legal category CD (Sch 4, Part I), POM

Prescribing costs (BNF Sep 2003) Nb – Dose in adult GHD usually between 0.2mg(0.6) and 0.6mg(1.8 iu) per day. Maximum dose rarely exceeds 1mg (3iu) per day. Also note – NutropinAq not listed in BNF as yet.

Product Description Amount Net Price Genotropin Two compartment cartridge containing 5.3mg (16iu) £122.87 powder for reconstitution, somatropin(rbe) and diluent for use with Genotropin pen As above 12mg (36iu) £278.20 MiniQuick – two compartment single- 0.2mg (0.6iu) £4.64 dose syringe containing powder for 0.4mg (1.2iu) £9.27 reconstitution, somatropin and diluent As above 0.6mg (1.8iu) £13.91 As above 0.8mg (2.4iu) £18.55 As above 1.0mg (3iu) £23.18 As above 1.2mg (3.6iu) £27.82 As above 1.4mg (4.2iu) £32.46 As above 1.6mg (4.8iu) £37.09 As above 1.8mg (5.4iu) £41.73 As above 2.0mg (6.0iu) £46.37 Humatrope Powder for reconstruction, somatropin 1.33mg (4iu) £30.50 vial with diluent As above 6mg (18iu) £137.25

As above 12mg (36iu) £274.50 As above 24mg (72iu) £549 Norditropin SimpleXx injection, somatotropin 3.3mg 1.5ml, 5mg £115.90 (10iu)/ml for use with Nordipen (15iu) SimpleXx injection, somatotropin 6.7mg 1.5ml, 10mg £231.80 (20iu)/ml for use with Nordipen (30iu) SimpleXx injection, somatotropin 10mg 1.5ml, 15mg £347.70 (30iu)/ml for use with Nordipen (45iu) Saizen Powder for reconstruction, somatotropin 1.33mg (4iu) £30.50 with diluent As above 3.33mg (10iu) £76.25 Click.easy powder for reconstitution, 8mg (24iu) £183 somatropin in click.easy device with diluent Zomacton Powder for reconstitution, somatotropin 4mg (12iu) £87.44 with diluent for use with ZomaJect needle free device or Auto-Jector or with needles and syringes Nutropin 10mg cartridge containing somatotropin 10mg (30iu) Not yet Aq in solution for use with Nuotropin pen produced in BNF References

1. Cuneo RC, Salomon F, McGauley GA, Sonksen PH. The growth hormone deficiency syndrome in adults. Clin Endocrinol (Oxf). 1992;37:387-97

2. Sonksen PH, Weissberger AJ, Varikious K. Diagnosing growth hormone deficiency in adults. The Somatotrophic Axis & the Reproductive Process in Health and Disease 1995. Spinger-Verlag

3. Lambers SWJ, Valk, NK, Binnerts A. The use of growth hormone in adults: a changing scene. Clin Endocrinol (Oxf). 1992;37:111-115

4. McGauley GA. Quality of life assessment before and after growth hormone treatment in adults with growth hormone deficiency. Acta Paediatr Scand Suppl 1989; 356: 70-2

5. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH. Growth hormone treatment in growth hormone deficient adults. Effects on exercise performance. J Appl Physiol 1991; 70:695-700

6. Bengtsson B-A, Eden S, Lonn L, Kvist H, Stokland A, Lindstedt G et al. Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab 1993; 76: 309-17