growth hormone therapy

Sympos ium on Growth and Its Disorders

Growth Hormone Therapy Anurag Bajpai 1 and P.S.N. Menon

1Division of Pediatric Endocrinology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India and Department of Pediatrics, Armed Forces Hospital, Kuwait.

Abstract . Growth hormone (GH) therapy has revolutionized treatment of children with growth hormone deficiency (GHD). Improved height outcome with final height in the target height range has been achieved in these children. Identification of Creutzfeldt-Jakob disease, a deadly prion mediated disorder, in recipients of pituitary GH accelerated the transition from pituitary derived GH to recombinant GH. Once daily subcutaneous administration of the freeze-dried preparation at evening is the recommended mode of GH therapy. Studies have led to use of higher dose of GH for improving height outcome (0.33 mg/kg/ week or 0.14 I U/kg/day) albeit at a significantly high cost. Growth velocity increases from 3-4 cm/year before therapy to 10- 12 cm/year during the first two years of therapy and is maintained at 7-8 cm/year after a period of two years. Close follow-up with regular clinical and laboratory monitoring is essential for achieving a desirable height outcome. A theoretical unlimited supply has led to wide spread use of GH in a variety of disorders other than GHD. Initially started in children with Turner syndrome, GH has now been used in chronic renal failure, idiopathic short stature and intrauterine growth restriction besides a wide array of newly emerging indications. [Indian J Pedlatr 2005; 72 (2) : 139-144] Emaih [email protected]

Key words : Growth hormone; Growth hormone deficiency; Idiopathic short stature; Tumer syndrome

Growth hormone (GH) therapy forms the cornerstone of management of children with growth hormone deficiency (GHD). Pituitary derived GH was used for over 25 years wi th remarkab le success. Limited supp ly h o w e v e r res t r ic ted its w i d e s p r e a d use. Iden t i f i ca t ion of Creutzfeldt-Jakob disease, a deadly p r ion-media ted disorder, in recipients of pituitary GH accelerated the transition from pituitary derived GH to recombinant GH. A theoretical unlimited supply has led to widespread use of GH in a variety of disorders other than GHD.

Route of Administration

Intramuscular route was initially recommended for GH due to the possible immunogenic effect of subcutaneous injection. Efficacy, pha rmacok ine t i c effects and immunogenic potential of subcutaneous injection of GH are s imilar to i n t r amuscu l a r admin i s t r a t ion . 1.2 Subcutaneous injection is currently the route of choice for GH administration. Trials on intranasal administration of GH are under way.

Time of Administration

Pituitary derived GH was administered two to three times in a week. Studies have shown that daily GH is superior to intermittent administration with regard to growth, IGF response and serum GH levels. 3 Twice daily GH has not been shown to be supe r io r to once daily. 4 Evening administration of GH leads to higher GH levels, greater

Correspondence and Reprint requests : Dr. P.S.N. Menon, Consultant & Chairman, Department of Pediatrics, Armed Forces Hospital, PO Box 5819, Salmiya 22069, Kuwait. Fax : (965) 4760324

IGF response and better metabolic profile compared to m o r n i n g or a f t e rnoon admin i s t r a t ion . -~ Once da i ly administration at evening is the recommended mode of GH therapy.

Preparations and Mode of Administration

Freeze-dried preparations are the commonest forms of GH avai lable . Liquid p r ep a ra t i o n s of GH have the advantage of ease of administration. A long acting analog of GH has shown promising results in initial studies. 6 GH has traditionally been injected with a syringe. Automated pen devices have the advantage of ease of administration, accuracy of dose and less inconvenience to the patient.

Dose Expression

The dose of GH has traditionally been expressed as uni t / kg/day. Recently there is a trend of using m g / k g / d a y or mg/m2/week for calculation of dose of GH. As per WHO standards 1 mg of recombinant GH has a bioactivi ty equiva len t to 3 IU. Expressing dose by surface area compared to body weight has the advantage of lower var ia t ion f rom infancy to ado lescence and is more representative of body requirement. 7 Estimation of GH dose accord ing to b o d y we igh t is in pa r t i cu la r nonphysiological in obese children as GH levels correlate negatively with body fat content. Despite these limitations GH dose is expressed according to body weight in most countries.

Dosage

The endogenous production rate of GH is variable and

Indian Journal of Pediatrics, Volume 72--February, 2005 139

Anurag Bajpai and P.S.N. Menon

ranges from 20 ~tg/kg/day during pre-pubertal period to 35 ~tg/kg/day during puberty? Dose of 0.16 mg /kg / week (0.07 I U / k g / d a y , 22 ~tg/kg/day) therefore represents physiological replacement dose for GH. Initial dose recommendations for patients with GHD have been based on these estimates. Studies on GH therapy in GHD have shown that this dose is unlikely to produce sustained catch-up growth and have led to use of higher dose for improving height outcome (0.33 mg/kg/week, 0.14 IU/kg/day, 45 Ilg/kg/day). In conditions other than GHD higher doses of GH are required to achieve pharmacological effects.

GH THERAPY IN DIFFERENT DISORDERS

The scope of GH therapy has been expanded dramatically in the last two decades with use in a variety of genetic syndromes, skeletal dysplasias and chronic diseases. GHD however remains the most important indication of GH therapy.

Growth Hormone Deficiency

GH therapy has been shown to significantly improve height outcome in GHD. Close follow-up with regular clinical and laboratory monitoring.is essential for achieving desirable height outcome.

Diagnosis

The diagnosis of GHD should be based on a combination of auxological and laboratory parameters. Compromised height (standard deviation score, SDS < -2) with low growth velocity (SDS < -1) in the presence of inappropriate response to two st imulation tests is required for establishing the diagnosis of GHD. 9 Recent recommendations suggest that peak GH levels below 10 ng/ml are diagnostic of GHD compared to previously used levels of 5-7 ng/ml.

Initiating Therapy

GH therapy should be initiated only after other anterior pituitary hormone deficiencies have been excluded or treated. Parents should be explained about the cost of therapy and the need of long-term follow-up. Giving GH for less than two years is futile and should be strongly discouraged. Initial GH dose is determined according to age, skeletal maturation and pubertal status of the patient. Thus while lower dose may be acceptable in a four-year- old child, higher doses are definitely indicated in a nine- year-old girl approaching puberty. Prediction models, a recent advance in the management of children with GHD, may be used for determining appropriate GH dose for the patient. ~~ Initial dose of 0.17-0.33 mg/kg/week (0.07- 0.14 IU/kg/day, or 4.6-9.2 mg/m2/week) has been used for treatment of GHD. Studies have however shown that higher doses of GH may be helpful in improving height outcome albeit at a significantly higher cost. ~2,13

Treatment of Concomitant Anterior Pituitary Deficiencies

Cortisol should be the first hormone to be replaced in a child with multiple pi tui tary hormone deficiency. Replacement doses of glucocorticoids in these patients (8- 12 mg/m2/day) are low compared to those with primary adrenal insufficiency (12-15 mg/m2/day) . Mineralocorticoid replacement is not required. Free thyroxine (FF4) levels should be maintained in the normal range. It is important to emphasize that overtly aggressive thyroid replacement may lead to inappropriate skeletal maturation and compromised height. Replacement of sex hormones should be delayed (12 years in girls and 14 years in boys) to provide adequate time for GH therapy.

Follow-up

Children on GH therapy should be followed-up every three months. Evaluation at each visit should include measurements of height, weight, height SDS, growth velocity SDS and assessment for complications of therapy. Bone age is of limited utility in follow-up of children on GH therapy except for the patient nearing completion of statural growth. IGF-1 and IGFBP-3 levels should be measured annually and maintained at high normal range for the age and gender of the child. ~4 GH therapy may unmask hypothyroidism in children with borderline thyroid status. Diabetogenic effect of GH may induce insulin resistance and result in impaired glucose tolerance or overt type 2 diabetes mellitus. Blood sugar and FT4 levels should be estimated after an interval of three, six and twelve months of initiation of GH therapy. Thereafter annual estimation of blood sugar and FT4 levels should be performed. It is important to emphasize that intra- cranial tumors may be missed on initial CNS imaging leading to a misdiagnosis of idiopathic GHD. These children should be closely monitored for development of features indicating CNS involvement.

Response to Therapy

GH therapy is associated with significant improvement in growth velocity, which increases from 3-4 cm/year before therapy to 10-12 cm/year during the first two years of treatment. ~s This catch-up response, however is not maintained and growth velocity declines to 7-8 cm/year after a period of two years. This apparent loss of effect of GH does not represent failure of therapy but demonstrates growth at a normal rate following correction of GH deficient state. ~6 Inappropriate response to GH therapy should prompt evaluation of compliance, injection technique, hypothyroidism or reconsideration of the diagnosis of GHD (Table 2). Decline in growth velocity following an initial increase suggest the possibility of unmasking of hypothyroidism while no response should prompt reconsideration of the diagnosis of GHD (Fig 1). Doses of GH should be adjusted according to growth velocity, pubertal status and IGF-1

140 Indian Journal of Pediatrics, Volume 72--February, 2005

G r o w t h H o r m o n e T h e r a p y

TASTE 1. Follow-up of Patients on GH Therapy

Parameter Frequency

Clinical Height SDS 3 months Growth velocity SDS 3 months Complications of therapy 3 months Injection technique, compliance 3 months

Laboratory Free thyroxine (FT4) At 3, 6 and 12 mo of therapy,

Annually thereafter Blood sugar Annually IGF-1, IGFBP-3 Annually

height SDS -1.3) compared to GH alone (height SDS - 2.7). ~ GnRH analog therapy should be used for a period of at least two years as treatment for shorter duration may lead to initial acceleration of puberty due to the agonist activity of the hormone.

Discont inuat ion of Therapy

GH therapy should be continued till final height has been achieved. Growth velocity below 2 cm in the preceding year with bone age of 14 years in girls and 16 years in boys is considered as indicator of final height. The issue of continuation of GH therapy during adulthood should be discussed with the family.

TAerE 2. Reasons for Poor Response to GH Therapy

Drug related Lower dose Poor compliance Improper technique Wrong diagnosis GHD type IA with anti GH antibodies

Effect on Final He ight

Disease related

Patient related

Complication related

Poor nutrition Malabsorption Hypothyroidism

12

~" 4

~2

0

GHD

thyrodism

J ~ Non-GHD

0 1 yr 2 yr 3 yr 4 yr

Treatment Duration (Years)

Fig 1. Response following GH therapy

61ff

and IGFBP-3 levels. Prediction models have been used for optimizing GH dose. 1~

Optimization of Therapy During Puberty

Puber ta l g rowth in chi ldren with GHD is similar to normal individuals27,~8 Compromised height at puberty is therefore invariably associated with compromised final height. Two different approaches have been tried for maximizing benefits of GH therapy in individuals who are short at the onset of puberty. In the first approach higher doses of GH (up to 0.15-0.2 IU/kg/day) have been used during puberty. 19 In a randomized controlled trial high dose GH during puberty (0.7 mg/kg /week , 0.3 IU/ kg/day) was associated with significantly higher growth velocity compared to lower dose (0.3 mg /kg /week , 0.13 I U / k g / d a y ) ? ~ Prolongation of puberty with the use of gonadotropin releasing hormone analogs forms the basis of the other approach. 21 In a randomized controlled trial combination of GnRH analog with GH for a period of three years was associated with better outcome (final

Studies involving a large number of patients with GHD have shown significant i m p r o v e m e n t in final height following GH therapy. 2~26 Most of these studies however have used historical controls for comparison. Untreated severe GHD is associated with final height SDS in the range of--4 to -6 while long term GH therapy is associated with final height SDS in the range of -1 to -2. This could translate in a height gain of 20-30 cm. The efficacy of GH in children with severe GHD remains unequivocal; its impact on milder forms of disease may not be as dramatic.

Factors In f luenc ing O u t c o m e

An understanding of factors influencing height outcome is helpful in appropriate management of these children. Studies have shown that early diagnosis, higher dose, higher target height SDS, greater height SDS at the time of onset of pube r ty and longer dura t ion of therapy are associated with better height outcome. 2~29 Height gain during first year of therapy is an important predictor of overall response. This emphasizes the need of appropriate management and close monitoring during initial part of GH therapy. Table 3 summar izes factors inf luencing height outcome in GHD and interventions directed at improving outcome. Children with combined pituitary deficiency have better height outcome compared to those with isolated GHD. ~ This may be due to delay in puberty due to concomitant gonadotropin deficiency.

TABrE3. Factors Influencing Height Outcome in GHD and Possible Intervention for Improving Outcome

Factor influencing outcome I m p a c t Intervention

Age at initiation Negative Early diagnosis Initial height SDS Positive Early diagnosis Height SDS at puberty Positive Pubertal height gain Positive GnRH analog,

higher dose Duration of therapy Positive Increase duration Dose Variable Higher dose Target height Positive - Height gain during first year Positive High initial dose,

close monitoring Multiple pituitary defects Positive


Anurag Bajpai and P.S.N. Menon

Cost of Therapy

One of the major limitations of GH therapy is high cost. In a study conducted in United States the cost of GH therapy for a 20 kg child with GHD was estimated to be $15,000 per year. In India the approximate cost for a 20 kg child would be Rs 200,000 per year. Cost considerations are the major limiting factors of wide spread use of GH therapy in resource-poor settings.

Adverse Effects

Recombinant G H has been shown to be safe during its w i d e s p r e a d use (Table 4). The mos t c o m m o n initial adverse effects include headache and vomit ing due to pseudotumor cerebri and edema due to fluid and sodium retention. 31 These effects improve over time without any intervention. It is however important to emphasize that headache in a child with a diagnosis of idiopathic GHD may be a pointer of an intra-cranial tumor and should p r o m p t a p p r o p r i a t e CNS imag ing . In i t ia l r epo r t s sugges ted an increased risk of l eukemia in subjects receiving GH; subsequent studies have however failed to substantiate these findings. 32-~ The use of GH in children with intra-cranial tumors is In particular a major cause of concern due to the theoretical possibility of reappearance of tumors. In a large study involving 1000 children with intra-cranial malignancy GH therapy was not associated with increased risk of tumor recurrence. ~ G H therapy may unmask hypothyro id i sm and induction of insulin resistance mandating the need of close follow-up for these complications dur ing therapy. 36 Slipped capital femoral ep iphyses and obstruct ive sleep apnea have not been shown to be h igher in children receiving G H therapy compared to children with GHD who are not on GH. 37~

Therapy F o l l o w i n g C o m p l e t i o n of Statural G r o w t h

Initially G H the rapy was l imited to pe r iods of active

growth. Recent studies have shown that GHD in adults is associated with significant complications in the form of risk of atherosclerosis, altered body composition and poor quality of life. 39 These complications improve with GH? ~ These observations have led to the recommendations of G H the rapy in adul ts wi th GHD. Retesting for G H D should be performed after discontinuing the drug for a period of 1 month. A significant number of children with isolated idiopathic G H D (50-70%) would not be G H deficient during re-testing. This may reflect inaccuracies of initial GH test on one hand and transient na ture of GHD on the other. Patients with peak GH levels below 3 n g / m l (cutoff levels for adults) should be started on 0.5 m g / d a y of GH. These recommenda t ions however are difficult to follow in resource-poor setting.

GH THERAPY IN NON-GHD SHORT STATURE

Turner S y n d r o m e

Turner syndrome was the first disorder besides GHD for which G H therapy was approved . Long- term studies have suggested significant improvement in final height following GH ranging from 4-9 cm over predicted height at init iat ion of therapy. 41-43 The dose of GH in Turner s y n d r o m e is higher c o m p a r e d to G H D (0.35 m g / k g / week or 0.15 I U / k g / d a y ) . Use of even higher dose (0.3 I U / k g / d a y ) has been shown to produce height gain in the range of 16 cm. 44 Early GH therapy is recommended for maximizing benefits. GH therapy should be started in girls with Turner syndrome when height falls below 5 th centile for the normal growth curve. GH stimulation test is not required. Oxandrolone (50 ~tg/kg/day) should be added after the age of 8 years. Early initiation of GH along with delayed induction of puber ty (at least four years a f t e r s t a r t i ng GH) c o m b i n e d wi th o x a n d r o l o n e is

TaSLE 4. Adverse Effects with GH Therapy

Adverse effect Incidence Suggested intervention

Psuedotumor cerebri* 0.16%/year Rule out CNS tumor Glucose intolerance 1% Reversible Slipped capital femoral epiphyses** 70-150/lO0000/year Orthopedic evaluation Hypothyroidism Thyroxin replacement Recurrence of tumor Unproven Delay treatment Second malignancy Unproven

* Higher in Turner syndrome and chronic renal failure ** Higher in organic GHD

TABLE 5. Benefits of GH Therapy for Established Indications

Disorder Indication Initial dose Benefit Evidence

GHD All subjects 0.07-0.1 IU/kg/d 15-20 cm Definite benefit Turner Height < 5 ~' centile 0.14-0.2 IU/kg/d 6-8 cm Definite benefit CRF All subjects 0.14-0.2 IU/kg/d 6-8 cm Unclear ISS Height SDS < -3 0.14-0.2 IU/kg/d 4-6 crn Questionable IUGR No catch up growth 0.10-0.2 IU/kg/d 8-10 cm Unclear Prader Willi All subjects 0.14-0.2 IU/kg/d 15-20 cm Definite benefit

CRF - Chronic renal failure, ISS - Idiopathic short stature, IUGR - Intrauterine growth restriction


Growth Hormone Therapy

associa ted wi th best he ight ou t come in Turner syndrome. 45

Chronic Renal Failure (CRF)

Chronic renal failure is associated with significant growth compromise that persists despite renal replacement therapy. High dose GH improves height ou tcome in children with CRF. ~ In a randomized controlled study involving 38 pre-pubertal children with CRF, treatment with GH led to increase in height SDS by 1.4 compared to decline in height SDS by 0.6 in the control group. 47 This response however is not sustained over a long period of time without kidney transplantation.

Idiopathic Short Stature (ISS)

Idiopathic short stature represents a mix of children with mild defects of the GH and IGF axis and low genetic potential. Marginal benefits have been reported with the use of GH. A gain of 5-7 cm compared to historical controls was observed in a s tudy using high dose GH (0.33 m g / k g / w e e k or 0.14 I U / k g / d a y ) . 4s In a meta- analysis involving 1089 patients with idiopathic short stature treated with GH height gain of 4-6 cm was noted. 49 The cost of therapy remains exorbitant at $13000 for every cm of height gained. Trial of GH therapy in children with idiopathic short stature should be continued for at least six months. The drug may be discontinued in children who do not show catch up growth. GnRH analog could be combined with GH for maximizing height gain.

Intra-uterine Growth Restriction (IUGR)

IUGR comprises of a heterogeneous mix of individuals with genetic, environmental and placental compromise. Majority of these patients show catch up growth with final height in the low normal range. However 15% of these individuals have compromised height and are at risk of shor t s tature. In a r a n d o m i z e d cont ro l trial invo lv ing 54 chi ldren wi th IUGR, GH the r apy was associa ted wi th increase in height SDS by 2 SDS. 5~ Importantly, children receiving lower dose (0.1 I U / k g / day) had similar height gain compared to those on higher dose (0.2 IU/kg/day) .

Prader-Willi Syndrome

Chi ld ren wi th this s y n d r o m e have s igni f icant complications like obesity, low muscle mass, hypotonia and compromised height. GH therapy in a dose of 0.1 IU/ k g / d a y has been associa ted with i m p r o v e d he ight outcome, fat mass, body composit ion and respiratory functions. 5~

Other Disorders

The list of d isorders for which GH has been used is increas ing every day. Favorable results have been reported in dysmorphic syndromes like Seckel and Silver Russel s y n d r o m e s and bone d isorders like skeletal dysplasia and hypophospha temic rickets. Long-term

ou tcome howeve r remains unclear in mos t of these conditions. GH therapy has also been tried in catabolic disorders like bums, HIV infection and anorexia nervosa.

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