Current State of Growth Hormone Therapy

Introduction 

Treatment of short stature, caused by pituitary insufficiency, with human growth hormone (hGH) was first reported by Raben in 1958.\ Over the following twenty-five years the number of patients treated increased, but the relative scarcity of the hormone limited its use mostly to investigational protocols and  the most severe forms of growth hormone (GH) deficiency. Transmission of a "slow virus", responsible for the development of a progressive neurological disease in a child treated with hGH was reported initially in 1981.2 Production and use of hGH was discontinued worldwide in 1985 because of the contamination of some batches of the hormone by the "virus" (prion) responsible for Creutzfeld-Jacob disease.' In the same year, biosynthetic growth hormone was approved for use and the numbers of patients treated increased rapidly. We briefly review the current status of growth promoting and anabolic uses of growth hormone in children and adults. 

Physiology of Growth Hormone 

Secretion of GH from the anterior pituitary is regulated by the stimulating and inhibitory effects of hypothalamic eptides growth hormone releasing hormone (GHRH) and somatotropin release inhibiting hormone (Somatostatin). It is secreted throughout life and is thought to have important physiologic functions even after growth is complete. GH circulates in the bloodstream bound to growth hormone binding protein (GHBP) that is the extracellular moiety of GH receptor. After binding to the receptor, GH stimulates the production of insulin-like growth factor-I (IGF-l) in the periphery, primarily liver. GH inhibits GHRH and both GH and IGF-l stimulate secretion of somatostatin. In circulation, IGF-l is bound to IGF-binding proteins (predominantly IGF-binding protein-3 [IGFBP-3]. GH itself has strong anabolic and lipolytic effects. Its growth promoting action however, is primarily mediated by IGF-l. In extra-hepatic tissues, such as the cartilage, GH stimulates IGF-l synthesis, which also can act locally to stimulate chondrogenesis and bone growth.l" 

Indications for Therapy 

The use of GH was initially limited to children with hypothalamic or pituitary abnormalities (Table I)YNow, in view of the virtually limitless supplies, indications for therapy have expanded in children and are extended to adults. Nonetheless, because GH continues to be very expensive, most countries have developed guidelines for its use. In children, GH is primarily used to enhance the rate of growth. In contrast, GH therapy in adults is based on its anabolic effects.4,8 The disorders in which GH is thought to be potentially beneficial are listed in Table 2. GHRH, used successfully for treatment of hypothalamic GH deficiency in a small number of children, is no longer available for therapeutic use. 

Growth Hormone Deficiency 

Children with growth hormone deficiency (GHD) have been successfully treated for over 40 years.6,7 Unfortunately, because concentrations of GH are low in random blood samples in both normal and GHD children, the diagnosis is at times arbitrary and diffcult.6,9"o Growth hormone is secreted from the pituitary in a pulsatile manner, the frequency of which correlates with the onset of deep sleep. 
Measurement of GH concentration every 10-20 minutes over 12-24 hours in GHD children has demonstrated both lower pulse frequency and amplitude compared to normal children. However there is an overlap between GHD and normal short children. In addition because the study is cumbersome, expensive, and labor intensive, it can be performed only under special umstances and has little practical value. Increased GH secretion in response to pharmacological stimuli has made provocative tests the cornerstone for the diagnosis.v"!' However, patients' responses may vary over time as well as with the agent used and stage of puberty. Variability in GH levels depending on the laboratory method used has made the diagnosis even more problematic. 
Childhood growth is GH dependent, thus growth hormone deficient children show a fall off in growth early in life. Severity ofGH deficiency correlates with the reduction in the rate of growth and response to treatment is often better in severely deficient children. However, otherwise normal short children may also have growth acceleration after institution of GH therapy.v' Treatment is instituted as soon as the diagnosis of GHD is established. Biosynthetic GH is marketed by several pharmaceutical companies worldwide. Depending on the manufacturer, the recommended dose is 0.16-0.3 mg/kg/week (0.48-0.9 IU/kg/ week) administered subcutaneously 6-7 days a week.5,6,11 Patients show a dramatic catchweek. 5,6, II Patients show a dramatic catch-up growth in the first year or two of therapy. The beneficial effect may wane after several years of therapy, but chi Idren show enhanced rate of growth with an increase in the dose.5,6 Rarely, there is little or no response to therapyll and treated children do not reach their genetic potential. Those diagnosed and treated at an earlier age have a better prognosis. In contrast, the more mature the skeleton at diagnosis, the poorer the final outcome.5,6,11,12 The diminishing beneficial effects on growth over time correlates with skeletal maturity rather than chronological age or duration of therapy.Y''!'

Turner's Syndrome

 Short stature is the single most common physical abnormality in Turner's syndrome (TS).13 Patients with 45 XO karyotype are shorter than those with mosaic TS. Growth failure is characterized by mild intra-uterine growth retardation, slow growth during childhood, and absent or delayed pubertal growth spurt.14-16 Untreated patients follow a percentile line on the TS curve throughout childhood and adolescence.F:" Adult height in untreated women is 143±4.1 cm (mean ± SO), about 20 cm shorter than their normal peers. 15,17 The underlying cause of short stature in TS is not known. Patients may have a blunted GH response to provocative stimuli but are not GH deficient. Treatment with GH accelerates the rate of growth and the final height is improved significantly. I 1,15 Addition of anabolic steroids (oxandrolone) may enhance     fici ff     10 I 5 19 Th     .. . these bene Ictal ertects, " erapy IS 1111- tiated as soon as height falls below the fifth percentile for age, usually at 2 -5 years of age. The dose of GH in TS is 20% higher than the dose in GH deficiency. Therapy is continued until the bone age exceeds 15 years or growth is and dose of estrogen rep acement.": e reported increase in final height is 5-16 cm.23,24 

Chronic Renal Failure 

Growth retardation is a common problem in children with chronic renal failure (CRF) and traditionally has been attributed to uremia, chronic acidosis, and malnutrition. Patients with CRF have partial GH insensitivity and low concentrations of IGF-l. In addition clearance of IGFBP-3 is decreased, resulting in lower concentrations of free IGF _l.25-27 Animal tudies showing that this relative GH resistance can be overcome by supraphysiologic doses of GH provided the rationale for the use of GH in chronic renal failure.6,11,27 Growth hormone stimulates growth in children with CRF and end-stage renal disease from 4 to 8 ern/year, in the first year of therapy.II,27,28 Treatment does not accelerate the rate of bone maturation. The beneficial effects are not attenuated by a strict low-protein, low-phosphate diet. Sixty-five percent of the children with CRF treated with GH reach a normal adult height." Children on either peritoneal dialysis or emodialysis, also respond to GH, however, the response is less pronounced and less persistent." Successful renal transplantation verses the uremic state and theoretically restores normal GH secretion and tunction.":" However growth failure, now caused by reduced graft function and glucocorticoids, often persists despite GH therapy.3D,31 The dose of GH used in CRF is 0.25-0.35 mg/kg/week given as daily subcutaneous injections (approximately 4 IU/m2 daily). Response is correlated with the child's renal function and target height, and inversely with the patient's age." 

Small for Gestational Age 

Children born small-for-gestational age (SGA) have a higher risk of short stature as adults than their normal weight peers. Al-though the majority have catch-up growth in early life, almost 15% continue to grow slowly and remain short.32-35 The cause of the failure to catch-up is not known. In several studies 50-60 % of SGA children aged 3-10 years had bnormal endogenous GH secretion.33-36 Concentrations of IGF-l are also lower in SGA children who fail to catch up 
suggesting a disturbance in the GH-IGF axis.37,38 If treated with GH, short SGA children have a rise in the concentrations oflGF- 1 and IGFBP-3. The levels decrease to baseline with the discontinuation of therapy.Y 4D The magnitude of response to treatment depends on the growth hormone dose, the age of the child (the younger, the more responsive) and the family-corrected individual height deficits." Growth hormone (O.I-OJ IU/kg/day) enhanced growth rate in short children born SGA and was greater in the group treated with a higher dose.32,36 Al- though long term studies on the impact of therapy on final height are not available, GHinduced acceleration of growth rate appears to be sustained. Children with SGA may have early puberty." Treatment with growth hormone may also influence the timing and duration of puberty. In addition, reatment appears to have positive effects on body mass ind     d linid     boli     611 Il1 ex an rpt meta 0 Ism. ' PraderWilli Syndrome Prader- Willi syndrome (PWS) is the most common known genetic cause of marked obesity (one in 10,000-15,000 live births).43,44 Almost 70% of patients have a deletion in q ll-q 13 region of paternal chromosome 15. Loss of the critical paternal region in the re- maining patients is brought about by maternal uniparental disorny." Clinical features include hyperphagia, hypotonia, hypogonadism, and developmental delay, as well as short stature.44,45 Affected children have abnormal body composition resembling GH deficiency.f" These finding, combined with the accompanying pothalamic disturbance, suggest that some manifestations of the PWS could be improved with GH therapy.45-47 Growth hormone in doses typically used in GHD (J mg/rrr'zday) improves growth, body composition, physical strength, and agility."' 51 The acquisition of new gross motor skills, appears to be important "real-life" benefits for these children.45,5D,51 Nonetheless, the perceived benefits in a developmentally delayed child, who may have little nderstanding of the rationale for therapy, must be weighed against the discomfort of therapy and its potential undesirable effects. 
Normal Short Children These children by definition do not have any abnormality in growth hormone secretion and action. Unfortunately because diagnosis of GHD is difficult, there is often an overlap between the groups. Otherwise normal short group is comprised of a heterogeneous group of children including those with familial or constitutional short stature and patients with subtle, and currently poorly understood or diagnosed abnormalities in GH secretion or action,6,52 Normal short children, if treated with GH, often have an acceleration of growth.52,53 Whether or not their final height improves as a result of therapy, however, is subject to dispute. The reported impact on the adult height has ranged from negative" to 5-6 ern mean increment.53 Multiple ethical, economic, and psychosocial issues are involved in the treatment of short normal children.52,53 Regardless of the absolute height of a population, a certain number of individuals fall below the 3rd or s" percentiles. Nonetheless, it is reasonable to offer a therapeutic trial of GH to those children who are very short (>3 SD below the mean).6,53

Dysmorphic Syndromes

Growth hormone has been used for the treatment of short stature in several dysmorphic syndromes including Aarskog," Rus-sell-Silver," Down,S7 and Noonan syndromes." Although some abnormalities in the GH-IGFaxis may be present, the majority of these children are not GH deficient. Nonetheless, enhanced rates of growth have been reported in all four groups of atients. The gene for Noonan syndrome, an autosomal dominant disorder with an incidence of one in 1,000-2,500, is mapped to chromosome 12.59 Initial response to therapy in this syndrome is similar to that seen in patients with Turner syndrome. 58 Steroid-Induced Short Stature Pathogenesis of growth failure caused by glucocorticoids is poorly understood. Steroids decrease retention of nitrogen and minerals, and inhibit bone formation. In addition they reduce GH receptor expression and signal transduction, and decrease IGF bioactiv.COCOrtlCOI -in uce growt 1 retardation is commonly seen in Cushing syndrome, as well as after prolonged use of exid 6) 63 ogenous sterol S.-' It has long been known that administration of large doses of steroids on alternate days can maintain their therapeutic benefit64 and yet ameliorate the undesirable effects on GH secretion or growth." More recently, better understanding of effects of steroids on GH secretion and action has increased interest in GH therapy. 
Growth hormone is beneficial for the rever- sal of the catabolic effects of glucocorticoids." Preliminary studies in children on relatively constant doses of steroids treated with GH for 12-24 months have shown nor malization of the growth rate."

Skeletal Dysplasia

Children and adults with various forms of skeletal dysplasia are very short but do not have an abnormality in the GH-IGFaxis. Response to GH therapy in a small number of patients has been modest and veariable.67,68 In one study, fourteen patients with achondroplasia treated for an average of 2.6 years, gained 0.75 SD in height." In another, growth velocity increased from 3.8 to 6 ern per year in the first year of treatment, decreasing to 4.4 ern/year in the second year.69 Although current data suggest that patients with skeletal dysplasia may respond to GH, the impact of therapy on adult height is not known.

Cystic Fibrosis

Growth failure in cystic fibrosis (CF) is the result of an unfavorable energy balance caused by the combination of low caloric intake, malabsorption, chronic pulmonary disd     ease an     increase energy expen iture. Concentrations of fGF -I are low and correlate with height SD score, body mass index, and Shwachman score (a clinical easure of disease activity)." In 1997, Hard in, et aI, reported increased linear growth and weight gain in prepubertal CF children treated with growth hormone for 1-2 years." In another study, treated patients had increased lean body mass, improved pulmonary function and fewer hospitalizations." However, impact of long-term GH therapy on pulmonary function and adult height remain unknown and the potential adverse effects of GH need to be considered.74,75 Increased risk of diabetes mellitus is of particular concern in these patients since the disease is relatively common in CF and growth hormone reduces insulin sensitivity. 76

Inflammatory Bowel Disease

Chronic inflammatory process, poor nutrition, and glucocorticoid therapy are thought to be responsible for short stature in children with Crohn's disease or ulcerative colitis." Growth promoting effects of GH in these pa.     h     b     . bl 77 78 S'     . trents ave een vana e.' mce patients have frequent exacerbation and changing nutritional state, it has been difficult to undertake large scale controlled studies. In a placebo cross over preliminary study, we treated seven children with Crohn's disease for 12- 24 months and found no significant beneficial effects (unpublished data). 
Juvenile Rheumatoid Arthritis Anecdotal evidence and our personal experience with a small number of patients with juvenile rheumatoid arthritis treated with GH suggests that some patients have an acceleration of growth rate." Whether or not long term GH has any value for the treatment of short stature in this disease is yet to be determined. 
Growth Hormone Deficiency in Adults Symptoms attributed to growth GHD in adults include fatigue, lack of energy, poor memory, inability to concentrate, feeling of social isolation, sexual disturbances, and emotional lability.Y'" Patients have increased fat, reduced lean body mass, decreased extracellular water and bone mineral density, and dyslipidemia and cardiac abnormalities. Impaired physical performance, reduced quality of life and psychological well-being, and decreased life expectancy are also common.82,83 Growth hormone given in relatively small doses (0.15-0.30 mg/day, 0.45-0.90 IU/day) to GHD adults is reported to have significant beneficial effects.83,84,86 Growth hormone decreases total cholesterol and low-density lipoprotein (LDL), and increases high-density lipoprotein (HDL) cholesterol. These changes are caused by upregulation of hepatic LOL receptors and increased clearance of very low density lipoprotein apolipoprotein." Treated GHD adults have increased exercise tolerance believed to be the result of increased lean body mass and improved lipid and carbohydrate metabolism.83,84 Treatment appears to have beneficial effects also on left ventricular size, stroke volume and cardiac output." An actual reduction in risk for cardiovascular events or mortality has not yet been demonstrated. Improvements in energy level, mood, emotional stability, vitality, and feelings of social isolation have also been reported. These beneficial effects on quality of life may potentially be the result of improvements in body composnon an p ysica perrorrnance. ' Diagnosis of GHD is more difficult in adults than in children because the former do not have poor growth as an indicator.9,lo.88 Since the criteria for GHD is different in adults, growth hormone deficient children should undergo additional provocative tests prior to consideration of life-long therapy." The recommended dose of GH is significantly lower in adults. Although GH is approved for therapy in adults it is prudent to use caution in its use. The effects of life-long treatment will not be known for years and the reported benefits must be weighed against the cost as well as the known and unknown undesirable effects.88,89 Growth Hormone in the Elderly There is a gradual decrease in GH secretion with age, and the metabolic profile in the elderly is similar to that of GH deficient patients.90,91 Growth hormone has been advocated by some to reverse the adverse effects .' owever, unti ong-term data are available, therapy should be iewed as investigational. 
Use of Growth Hormone by Athletes Athletes have used GH surreptitiously because of its known effects on body compos i- 
t    '     d     I     9?•94 Eff     . Ion an musc e mass. - Icacy to l Il- crease either muscle power or endurance has not been proven, Use of GH is banned by most international athletic organizations. 
Growth Hormone Therapy for Pro- tein Catabolism Increased catabolism is common in multiple acute and chronic disorders. Nutritional status is an important predictor of outcome in the critically i II and those with cancer or organ failure. Protein loss results in compromised mucosal integrity, defective immune response, poor healing, and muscle weakness. Protein catabolism is accelerated in a variety of conditions, including sepsis, burns, trauma, surgery, organ failure, and HIV infection. When prolonged, it results in an increase in morbidity and mortality.95.97 Growth hormone has been used with some success to improve the nutritional state of b    •     .     9596 I h US' I cata 0 IC patients.": n t e .. It ras been approved for the treatment of wasting in patients with AIDS.97 Short courses of growth hormone (10 IVlm2/day) increase nitrogen retention and net protein synthesis, and preserve lean body mass." Most studies have reported metabolic benefits as endpoints. Favorable clinical effects include decreased hospital stay and mortality in burns, improved espiratory function in chronic obstructive airway disease, preserved strength post-operatively, enhanced cardiac and bowel function, and reversal of tissue wasting in HIV disease.":" The enthusiasm for the use of GH in critical illness however, has been dampened by the report of a marked increase mortality in GH reated critically ill adults."

Undesirable Effects of Growth

Hormone Growth hormone therapy in children has generally been safe.loo Long-term studies have failed to show a higher incidence of malignancies. There is increased risk of benign intracranial hypertension (pseudotumor cerebri) and of slipped capital femoral epiphySiS.5,6,11 The incidence of each is about one in 700 patients. Weight gain, unrelated to fluid retention, is seen in some patients. Other adverse effects include pancreatitis, and benign     .     d     . 6 I 180101 GI     . pigmente nevI.' , , ucose intolerance and Type II diabetes mellitus have also been reported but the absolute risks appear to be 10? low. - Several years ago a report from Japan suggested a doubling of risk of leukemia in GH treated children.l03 Extensive worldwide search however has failed to confirm hi 680100104105 trns." , , , A recent report, on a cohort of 1848 patients treated with human growth hormone in the United Kingdom between 1959 and 1985, showed increased risk of colorectal cancer as well as increased mortality from Hodgkin disease and colorectal cancer.106 It has been estimated that almost 100,000 children have been treated and previous studies have failed to show an association between GH therapy and cancer.l'" Additional undesirable effects are more common in adults and include fluid retention, arthralgia, carpal tunnel syndrome, paresthesia and glucose intolerance.88,89 These are generally transient and dose-dependent, and respond to a reduction in GH dose.

Conclusion