Growth hormone therapy - medIND

S y m p o s i u m on G r o w t h and Its Disorders

Growth Hormone Therapy Anurag Bajpai 1 and P.S.N. M e n o n

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 IU/kg/day) albeit at a significantly high cost. Growth velocity increases from 3-4 cm/year before therapy to 1012 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 with r e m a r k a b l e success. Limited s u p p l y h o w e v e r r e s t r i c t e d its w i d e s p r e a d use. I d e n t i f i c a t i o n of Creutzfeldt-Jakob disease, a d e a d l y p r i o n - m e d i a t e d 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, p h a r m a c o k i n e t i c effects and immunogenic potential of subcutaneous injection of GH are similar to i n t r a m u s c u l a r a d m i n i s t r a t i o n . 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 b e e n s h o w n to be s u p e r i o r to once daily. 4 E v e n i n g 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 Indian Journal of Pediatrics, Volume 72--February, 2005

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

Preparations and Mode of Administration Freeze-dried preparations are the commonest forms of G H available. Liquid p r e p a r a t i o n s of G H h a v e 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 unit/ kg/day. Recently there is a trend of using m g / k g / d a y or m g / m 2 / w e e k for calculation of dose of GH. As per WHO standards 1 mg of recombinant G H has a bioactivity e q u i v a l e n t to 3 IU. Expressing dose by surface area compared to b o d y weight has the advantage of lower v a r i a t i o n f r o m infancy to a d o l e s c e n c e and is m o r e representative of body requirement. 7 Estimation of GH dose a c c o r d i n g to b o d y w e i g h t is in p a r t i c u l a 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 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 m g / k g / week (0.07 I U / k g / d a y , 22 ~ t g / k g / d a y ) 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.

Treatment of Concomitant Anterior Pituitary Deficiencies Cortisol should be the first hormone to be replaced in a child with multiple pituitary hormone deficiency. Replacement doses of glucocorticoids in these patients (812 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

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 stimulation 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.

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. ~4GH 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 intracranial 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.

Initiating Therapy

Response to 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-yearold child, higher doses are definitely indicated in a nineyear-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 m g / k g / w e e k (0.070.14 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

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. ~6Inappropriate 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

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

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

Growth

Hormone

TASTE1. Follow-up of Patients on GH Therapy Parameter

height SDS -1.3) c o m p a r e d 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.

Frequency

Clinical

Height SDS Growth velocity SDS Complications of therapy Injection technique, compliance

3 months 3 months 3 months 3 months

D i s c o n t i n u a t i o n of Therapy

Laboratory

Free thyroxine (FT4)

At 3, 6 and 12 mo of therapy, Annually thereafter Annually Annually

Blood sugar IGF-1, IGFBP-3

TAerE2. Reasons for Poor Response to GH Therapy

Disease related Patient related Complication related

Poor nutrition Malabsorption Hypothyroidism

12

thyrodism ~2 0

J 0

~ 1 yr

2 yr

Non-GHD 3 yr

4 yr

Studies involving a large number of patients with GHD have s h o w n significant i m p r o v e m e n t in final height following GH therapy. 2~26Most of these studies however have used historical controls for comparison. Untreated severe G H D 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 G H D remains unequivocal; its impact on milder forms of disease may not be as dramatic. Factors I n f l u e n c i n g O u t c o m e

GHD

~" 4

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. Effect o n Final H e i g h t

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

Drug related

Therapy

61ff

Treatment Duration (Years)

Fig 1. Response following GH therapy

and IGFBP-3 levels. Prediction models have been used for optimizing GH dose. 1~ Optimization of Therapy During Puberty Pubertal g r o w t h in children with G H D 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 I U / k g / d a y ) have been used during puberty. 19In a randomized controlled trial high dose GH during puberty (0.7 m g / k g / w e e k , 0.3 IU/ kg/day) was associated with significantly higher growth velocity compared to lower dose (0.3 m g / k g / w e e k , 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 Indian Journal of Pediatrics, Volume 72--February, 2005

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 p u b e r t y and longer d u r a t i o n of t h e r a p y are associated with better height outcome. 2~29Height 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 s u m m a r i z e s factors influencing 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

Impact

Intervention

Age at initiation Initial height SDS Height SDS at puberty Pubertal height gain

Negative Positive Positive Positive

Early diagnosis Early diagnosis

Duration of therapy Dose Target height Height gain during first year

Positive Variable Positive Positive

Multiple pituitary defects

Positive

GnRH analog, higher dose Increaseduration Higher dose High initial dose, close monitoring

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Anurag Bajpai and P.S.N. Menon Cost of T h e r a p y

One of the major limitations of GH therapy is high cost. In a study conducted in United States the cost of G H therapy for a 20 kg child with G H D 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 G H therapy in resource-poor settings. A d v e r s e Effects

Recombinant G H has been s h o w n to be safe during its w i d e s p r e a d use (Table 4). The m o s t c o m m o n initial adverse effects include headache and v o m i t i n g 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 G H D m a y be a pointer of an intra-cranial t u m o r and should p r o m p t a p p r o p r i a t e CNS i m a g i n g . Initial r e p o r t s s u g g e s t e d an i n c r e a s e d risk of l e u k e m i a in subjects receiving GH; subsequent studies have however failed to substantiate these findings. 32-~The use of G H 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 G H therapy was not associated with increased risk of t u m o r recurrence. ~ G H therapy m a y u n m a s k h y p o t h y r o i d i s m and induction of insulin resistance mandating the need of close follow-up for these complications during therapy. 36 Slipped capital femoral e p i p h y s e s and obstructive sleep a p n e a h a v e not b e e n s h o w n to be higher in children receiving G H t h e r a p y compared to children with G H D 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 t h e r a p y w a s limited to p e r i o d s 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 G H ? ~ These observations have led to the recommendations of G H t h e r a p y in adults with G H D . Retesting for G H D should be performed after discontinuing the d r u g for a period of 1 month. A significant number of children with isolated idiopathic G H D (50-70%) w o u l d not be G H deficient during re-testing. This m a y reflect inaccuracies of initial G H test on one h a n d and transient nature of G H D on the other. Patients with peak G H 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 r e c o m m e n d a t i o n s h o w e v e r 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 G H D for which G H therapy was a p p r o v e d . L o n g - t e r m studies h a v e suggested significant i m p r o v e m e n t in final height following G H ranging from 4-9 cm over predicted height at initiation of therapy. 41-43The dose of G H in T u r n e r 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 s h o w n to produce height gain in the range of 16 cm. 44 Early G H therapy is r e c o m m e n d e d for maximizing benefits. G H therapy should be started in girls with Turner syndrome when height falls below 5 th centile for the normal growth curve. G H stimulation test is not required. Oxandrolone (50 ~tg/kg/day) should be added after the age of 8 years. Early initiation of G H along with delayed induction of p u b e r t y (at least four years a f t e r s t a r t i n g G H ) c o m b i n e d w i t h o x a n d r o l o n e is

TaSLE4. Adverse Effects with GH Therapy Adverse effect

Incidence

Suggested intervention

Psuedotumor cerebri* Glucose intolerance Slipped capital femoral epiphyses** Hypothyroidism Recurrence of tumor Second malignancy

0.16%/year 1%

Rule out CNS tumor Reversible Orthopedic evaluation Thyroxin replacement Delay treatment

70-150/lO0000/year Unproven Unproven

* Higher in Turner syndrome and chronic renal failure **Higher in organic GHD TABLE5. Benefits of GH Therapy for Established Indications Disorder

Indication

Initial dose

Benefit

Evidence

GHD Turner CRF ISS IUGR Prader Willi

All subjects Height < 5~'centile All subjects Height SDS < -3 No catch up growth All subjects

0.07-0.1 IU/kg/d 0.14-0.2 IU/kg/d 0.14-0.2 IU/kg/d 0.14-0.2 IU/kg/d 0.10-0.2 IU/kg/d 0.14-0.2 IU/kg/d

15-20 cm 6-8 cm 6-8 cm 4-6 crn 8-10 cm 15-20 cm

Definite benefit Definite benefit Unclear Questionable Unclear Definite benefit

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

142


Growth Hormone Therapy a s s o c i a t e d w i t h best h e i g h t o u t c o m e in T u r n e r syndrome. 45

Chronic Renal Failure (CRF) Chronic renal failure is associated with significant growth c o m p r o m i s e that persists despite renal r e p l a c e m e n t therapy. High dose G H i m p r o v e s height o u t c o m e 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 c o m p a r e d to historical controls was observed in a study 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 metaanalysis 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 d r u g m a y 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 g r o w t h with final height in the low normal range. H o w e v e r 15% of these individuals have compromised height and are at risk of s h o r t stature. In a r a n d o m i z e d c o n t r o l trial i n v o l v i n g 54 c h i l d r e n w i t h IUGR, G H t h e r a p y w a s a s s o c i a t e d w i t h i n c r e a s e in h e i g h t 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 I U / k g / d a y ) .

Prader-Willi S y n d r o m e C h i l d r e n w i t h this s y n d r o m e h a v e s i g n i f i c a n t complications like obesity, low muscle mass, hypotonia and compromised height. GH therapy in a dose of 0.1 I U / k g / d a y has been a s s o c i a t e d with i m p r o v e d h e i g h t outcome, fat mass, b o d y composition and respiratory functions. 5~

Other Disorders The list of d i s o r d e r s for w h i c h GH has been used is i n c r e a s i n g e v e r y day. F a v o r a b l e results h a v e b e e n reported in dysmorphic syndromes like Seckel and Silver Russel s y n d r o m e s a n d b o n e d i s o r d e r s like skeletal dysplasia and h y p o p h o s p h a t e m i c rickets. Long-term


o u t c o m e h o w e v e r r e m a i n s u n c l e a r in m o s t of these conditions. GH therapy has also been tried in catabolic disorders like bums, HIV infection and anorexia nervosa.

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