Clinical Advances in Pediatric Endocrinology: Focus on: Growth Hormone Deficiency

Introduction The Pathophysiology of Growth Hormone Deficiency Mark A. Sperling, MD The Genomics of the GH/IGF-I Axis Ron G. Rosenfeld, MD New Paradigms for the Treatment of Growth Hormone Deficiency Pinchas Cohen, MD

Introduction

Growth hormone therapy has been available for 50 years, and with that milestone came the dawn of a new era in diagnosing and managing patients with short stature. Despite decades of experience, pediatric endocrinologists continue to be perplexed by seemingly simple criteria such as the distinction between normal and pathological short stature. However, advances are being made and clinicians are finally beginning to understand the physiological and molecular bases of growth disorders. These advancements herald the advent of a personalized medicine approach to growth disorders, and practitioners are looking forward to a time when the appropriate therapy can be matched to the underlying pathophysiology of each patient.

It is essential for health care practitioners who diagnose and manage patients with growth disorders to assure they are informed of the advances that are rapidly occurring in this dynamic and complicated field. To provide a platform for discussing salient aspects of growth hormone deficiency and treatment, Vindico Medical Education organized a panel of growth disorder experts to share their experience and expertise, focusing on pathophysiology, genomics, and new treatment paradigms.

I thank the panel for their contributions to the discussion and the development of this monograph, which will provide the reader with a state-of-the-art update on the etiology, diagnosis, and management of growth disorders.

Mark A. Sperling, MD
Course Chair

Course Chair: Mark A. Sperling, MD Professor and Chair Emeritus Department of Pediatrics Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania Ron G. Rosenfeld, MD Professor and Chair (emeritus) of Pediatrics Oregon Health & Science University Portland, Oregon Professor of Pediatrics (emeritus) Stanford University Palo Alto, California Pinchas Cohen, MD Professor and Chief of Endocrinology Mattel Children’s Hospital at UCLA David Geffen School of Medicine at UCLA Los Angeles, California

The Pathophysiology of Growth Hormone Deficiency

Mark A. Sperling, MD

Growth hormone (GH), also known as somatotropin, is a 191-amino acid protein that is synthesized and secreted by the anterior pituitary gland.¹ Two main variants circulate in blood, with molecular weights of 20 kDa and 22 kDa. Typically, 70% to 75% of pituitary-secreted GH is in the 22-kDa form, while the 20-kDa form is the second largest contributor to the circulating GH pool. As its name implies, GH promotes growth. Due to its growth-stimulating properties, an excess causes acromegalic gigantism; chowever, in pediatrics, deficiency of GH causing postnatal growth failure is encountered more frequently, and investigation is warranted in children who present with growth retardation.²

The Molecular Basis of GH Action

Regulation of GH secretion

The release of GH is controlled by growth hormone releasing hormone (GHRH) and somatotropin releasing inhibiting factor (SRIF), also known as somatostatin, which interact to generate pulsatile waves of GH release.³ Peak levels of 20 ng/mL to 25 ng/mL occur during sleep; therefore, sleep is a major physiological regulator of GH release. In addition, ghrelin, secreted primarily from the stomach during fasting, stimulates GH release by interacting with the GH secretagogue receptor (GHSR). Several other factors, such as stress, puberty, obesity, and a variety of signaling molecules modulate GH release, resulting in a complex network of the regulation of GH secretion (Figure 1, Table 1).

Figure 1. Beyond High Cholesterol and Hypertension: Factors Responsible for Atherosclerosis and the Induction of Acute MI in Diabetes A properly functioning interaction among insulin, GH, and IGF-I is critical for normal growth and metabolism. Source: Mark A. Sperling, MD

Between the pulses of pituitary GH secretion, serum GH concentrations are usually below the levels deemed indicative of GH deficiency and occasionally below the sensitivity of most conventional assays, creating a challenge in the diagnosis of GH deficiency (GHD) on random blood sampling. Accordingly, GH provocation tests are necessary to allow evaluation of adequate GH secretion in response to stimulation, and thereby can provide adequate diagnostic sensitivity for diagnosing GH deficiency.

Table 1. Regulation of the GH/IGF-I Axis Source: Mark A. Sperling, MD

The GH/Insulin-like Growth Factor-I Axis

Although between 30% and 50% of GH action is by direct stimulation of the growth plate, the remaining 50% to 70% is generated indirectly through insulin-like growth factor I (IGF-I); that is, its main growth effects are mediated through the GH/IGF-I axis (Figure 1). Insulin regulates the expression of the GH receptor (GHR) in the liver and stimulates IGF-I. IGF-I inhibition occurs with malnutrition and other illnesses. Circulating IGF-I deficiency also occurs with GH receptor deficiency and IGF-I action is impaired when there are defects in the IGF-I receptor. Although IGF-I concentrations correlate with pulsatile GH secretion in prepubertal and pubertal children, these inhibitory conditions impact the ability to accurately measure IGF-I.⁴ For example, in a patient who is acutely ill, undernourished, or has poorly controlled diabetes, a false-positive diagnosis of GHD is possible.

A properly functioning interaction among insulin, GH, and IGF-I is critical for normal growth and metabolism. GH requires insulin for expression of its receptors, which activate IGF-I, leading to the mediation of some, but not all, of the actions of GH. The synergy between insulin and GH that results in the stimulation of growth and development of bone and muscle mass occurs at lower GH concentrations than would be required in the absence of IGF-I.

Structural homology exists between IGF-I and the insulin receptors. Both are heterotetromers consisting of pairs of alpha and beta subunits. Both can bind the IGF-II molecule; in addition, at high concentrations each ligand can cross-react with the other’s receptor. Moreover, insulin and IGF-I can bind to hybrid receptors comprising half insulin receptor and half IGF-I receptor, thereby being able to respond to all 3 ligands.

Insulin-like growth factor binding protein-3 (IGFBP-3), the production of which is also regulated by GH, controls IGF-I bioactivity by increasing its half-life. It is the primary binding protein for IGF-I and IGF-II in the circulation. The serum IGFBP-3 concentration is also useful in the diagnosis of GH deficiency in children and is less age dependent and more sensitive (96%) and more specific (97%) than IGF-1.⁵

Metabolic Effects of GH

Sites of action

GH has a number of important metabolic effects. Acute and chronic elevation of serum GH levels cause insulin resistance. In adipose tissue, GH is lipolytic and decreases glucose transport, thereby inducing insulin resistance (Figure 2). This insulin antagonism can be compensated by increased insulin secretion by the pancreas. GH also antagonizes the effects of insulin on carbohydrate metabolism.⁶ In muscle, GH exerts anabolic effects by increasing amino acid transport and nitrogen retention, thereby increasing lean tissue mass. Although its activity is augmented by IGF-I, GH can act directly in the absence of IGF-I. In bone, GH causes bone-mineral accretion and increased bone mass. A “dual effector” theory proposes a direct action of GH in stimulating the differentiation of prechondrocytes, which cannot be achieved by IGF-I.^7,8 The subsequent local expression of IGF-I induces clonal expansion of osteoblasts. Accordingly, the 2 effectors cause tissue growth by first creating newly differentiated cells and then promoting their multiplication.

Figure 2. Multiple Sites of Growth Hormone Action Growth hormone exerts numerous affects on bone, metabolism, linear growth, muscle, and adipose tissue. Source: Allen DB. Growth Hormone Treatment. In: Lifshitz, F (eds). Pediatric Endocrinology. 4th edition. New York, NY. Marcel Dekker Inc. 2003;87-111.

GH during puberty

In puberty, increased GH secretion is manifested as an increase in the pulse amplitude of the nocturnal sleep-entrained secretion. The resulting insulin resistance that accompanies the increased GH levels is compensated by increased insulin secretion, which augments the growth-promoting effects of GH alone and in conjunction with sex steroids, produces the final physical shape and the differentiation between male and female growth.

Rates of glycerol production are markedly increased in pubertal as compared to prepubertal children. In addition to a significant increase in lipolysis (glycerol rate of appearance expressed as ?mol/m²/min), fatty acid oxidation over glucose oxidation is also significantly increased in puberty as compared to prepuberty.⁹ This is accompanied by a drop in circulating free fatty acids, as the fatty acids produced by GH are metabolized, sparing amino acids and glucose for other effects including growth.

The Patient with Short Stature

There are numerous causes of short stature, and diagnosing its etiology requires diligent consideration of predisposing conditions. The diagnostic approach begins with establishing that the patient is short for the age, family, and society (Figure 3). If both parents are in the lowest percentiles, based on our current understanding of the genes that regulate growth, their children would more likely be short compared with a child who comes from a family where both parents are tall. However, with greater understanding of the pathophysiology of abnormal growth and molecular defects of the GH-IGF-I axis at multiple levels, the less clear the dividing line between pathology and normal variation becomes. For example, if a mother is -4 SD and the father -3 SD, an offspring who is -4 SD should not be dismissed as a normal variant; a combination of mild genetic defects may be contributing to the child’s short stature. Because it is not always clear where normalcy ends and pathology begins, practitioners must consider all aspects of each patient’s situation.

Figure 3. Diagnostic Approach to Short Stature Diagnosis of the patient with short stature is methodical and involves consideration of all potential etiologies of short stature. Source: Mark A. Sperling, MD

Another normal variant that must be excluded is constitutional growth delay; that is, short stature with normal height velocity in early childhood followed by a delay in the growth spurt that normally accompanies puberty. Affected children may ultimately achieve a height appropriate for their family genetic background. Patients with constitutional delay may not require an extensive evaluation and may not require intervention.

The 2007 Idiopathic Short Stature Consensus Workshop produced a summary of important advances in the management of children with idiopathic short stature (ISS).¹⁰ The experts agreed that the separate terms, constitutional delay of growth and puberty and familial short stature, no longer serve the health care community. Accordingly, per this consensus statement, these conditions are now included in the definition of ISS.

Once the possibility of normal variants is excluded, differentiation between proportionate and disproportionate short stature is important in a patient with pathological short stature whose height is 2.5 SD to 3 SD below the mean. Disproportionate short stature typically implies skeletal dysplasia, but can also occur in cases of rickets and severe hypothyroidism.

Proportionate short stature can occur pre- and/or postnatally. Most prenatal cases are not due to GHD, although they can result from IGF-I or IGF-I receptor deficiency.

GHD most adversely affects postnatal growth. Therefore, children with congenital GHD are usually normal-sized at birth. Other characteristics, such as hypoglycemia, prolonged jaundice, or microphallus in males, may be present that can provide clinical clues, prompting an investigation of GHD and hypopituitarism.^11,12

There are additional causes of postnatal short stature that must be excluded, including malnutrition and chronic diseases such as gastrointestinal malabsorption, celiac disease, and inflammatory bowel disease. Renal, hematological, and other endocrine disorders should also be ruled out. Pharmaceutical agents, in particular those used for attention deficit disorder, may have mild effects on growth.

GHD

GHD can be congenital or acquired. Congenital GHD may be genetic or associated with structural defects of the brain. Most of these occur as a form of holoprosencephaly or other midline facial cleft syndrome defects, including agenesis of the corpus callosum and optic nerve hypoplasia (with or without absence of the septum pellucidum). Vision impairment, often presenting with nystagmus after a few months of life, is a characteristic occurrence in optic nerve hypoplasia.

GHD can be acquired in a variety of ways. For example, most patients with craniopharyngioma have GHD, and craniopharyngioma is the most common tumor in the hypothalamic-pituitary region that produces GHD in children.¹³ Optic nerve glioma may also cause GHD, which is commonly encountered in patients with neurofibromatosis.¹⁴ In the newborn period, GHD can be acquired due to trauma peri- or postnatally; accordingly, it is important to inquire about difficult delivery, particularly those with vaginal bleeding, breech presentation, or forceps delivery.¹⁵ Acute presentations of hypothermia, hypoglycemia, or shock may be associated with hypopituitarism. All of these causes should be considered in deciding whom to screen for GHD.

Conclusion

Endocrinologists agree that the definition of short stature is arbitrary. No one can truly say where the normal range ends and pathology begins; in fact, with each advance in understanding the physiology and genomics of growth, the dividing line becomes increasingly blurred. Although some pieces of the puzzle that constitute the normal physiology of growth are in place, there are many others still missing.

References

1. Rosenfeld RG, Cohen P. Disorders of Growth Hormone/Insulin-like Growth Factor Secretion and Action. In: Sperling M (eds). Pediatric Endocrinology. 3rd ed. Amsterdam, The Netherlands: Elsevier; 2008; 254-334.
2. Goldenberg N, Barkan A. Factors regulating growth hormone secretion in humans. Endocrinology and Metabolism Clinics of North America. 2007 Mar;36(1):37-55.
3. Sherlock M, Toogood AA. Aging and the growth hormone/insulin like growth factor-I axis. Pituitary. 2007;10(2):189-203.
4. Kawai N, Kanzaki S, Takano-Watou S, Tada C, Yamanaka Y, Miyata T, Oka M, Seino Y. Serum free insulin-like growth factor I (IGF-I), total IGF-I, and IGF-binding protein-3 concentrations in normal children and children with growth hormone deficiency. The Journal of Clinical Endocrinology and Metabolism. 1999 Jan;84(1):82-9.
5. Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel HJ, Bierich JR. A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency. The Journal of Clinical Endocrinology and Metabolism. 1990 May;70(5):1292-8.
6. Rizza RA, Mandarino LJ, Gerich JE. Effects of growth hormone on insulin action in man. Mechanisms of insulin resistance, impaired suppression of glucose production, and impaired stimulation of glucose utilization. Diabetes. 1982 Aug;31(8 Pt 1):663-9.
7. Green H, Morikawa M, Nixon T. A dual effector theory of growth-hormone action. Differentiation; Research in Biological Diversity. 1985;29(3):195-8.
8. Spagnoli A, Rosenfeld RG. The mechanisms by which growth hormone brings about growth. The relative contributions of growth hormone and insulin-like growth factors. Endocrinology and Metabolism Clinics of North America. 1996 Sep;25(3):615-31.
9. Hannon TS, Janosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Pediatric Research. 2006 Dec;60(6):759-63. Epub 2006 Oct 25.
10. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, Chernausek SD, Savage MO, Wit JM; 2007 ISS Consensus Workshop participants. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. The Journal of Clinical Endocrinology and Metabolism. 2008 Nov;93(11):4210-7. Epub 2008 Sep 9.
11. Wit JM, van Unen H. Growth of infants with neonatal growth hormone deficiency. Archives of Disease in Childhood. 1992 Jul;67(7):920-4.
12. Rosenfeld RG, Belgorosky A, Camacho-Hubner C, Savage MO, Wit JM, Hwa V. Defects in growth hormone receptor signaling. Trends in Endocrinology and Metabolism. 2007 May-Jun;18(4):134-41. Epub 2007 Mar 27.
13. Thomsett MJ, Conte FA, Kaplan SL, Grumbach MM. Endocrine and neurologic outcome in childhood craniopharyngioma: Review of effect of treatment in 42 patients. The Journal of Pediatrics. 1980 Nov;97(5):728-35.
14. Brauner R, Malandry F, Rappaport R, Zucker JM, Kalifa C, Pierre-Kahn A, Bataini P, Dufier JL. Growth and endocrine disorders in optic glioma. European Journal of Pediatrics. 1990 Sep;149(12):825-8.
15. Fujita K, Matsuo N, Mori O, Koda N, Mukai E, Okabe Y, Shirakawa N, Tamai S, Itagane Y, Hibi I. The association of hypopituitarism with small pituitary, invisible pituitary stalk, type 1 Arnold-Chiari malformation, and syringomyelia in seven patients born in breech position: a further proof of birth injury theory on the pathogenesis of "idiopathic hypopituitarism". European Journal of Pediatrics. 1992 Apr;151(4):266-70.

The Genomics of the GH/IGF-I Axis

Ron G. Rosenfeld, MD

Genetic causes of growth failure can be broadly divided into 5 categories: chromosomal defects such as Down syndrome and Turner syndrome, inborn metabolic defects, osteochondrodysplasias, genetic defects of the thyroid axis that result in neonatal or childhood hypothyroidism, and genetic defects of the growth hormone (GH)/ insulin-like growth factor-I (IGF-I) axis.

The GH/IGF-I Axis

The GH/IGF-I axis begins with GH secretion under the influence of hypothalamic factors. GH circulates in the bloodstream bound to GH binding protein. GH binds to and activates a GH receptor (GHR), initiating a complex signaling cascade that is still incompletely understood, but that ultimately leads to IGF-1 gene expression, IGF-1 secretion, and normal growth.

Data from both animal knockout studies and human mutational analyses suggest that the IGF system provides the major impetus for both intrauterine and postnatal growth.¹ Accordingly, it is practical to determine whether a child presenting with unexplained growth retardation has IGF-I deficiency, the consequence of which is short stature. IGF-I deficiency can be manifested at several locations in the GH/IGF-I axis. Primary IGF-I deficiency can result from interruptions in GHR binding or activation, post-receptor signaling, or IGF-I gene expression.

Secondary IGF-I deficiency stems from a defect in GH secretion. Genetic causes of secondary IGF-I deficiency can be attributed to isolated growth hormone deficiency (GHD) due to GH gene deletions, GH mutations, bioinactive GH, or defects of the GH releasing hormone receptor (GHRHR). cAlternatively, it can result from multiple pituitary hormonal deficciency (MPHD) including mutations of specific genes such as LHX3, LHX4, HESX1, PROP1, POU1F1, and SOX3.

Some cases of MPHD may present initially with only GHD or as a combination of GH and thyroid stimulating hormone deficiency, with gonadotrophin and adrenocorticotropin hormone deficiencies becoming clinically evident later or not at all. MPHD may evolve over several years. Therefore, children who are initially identified as having isolated GHD may evolve into MPHD. There may be phenotype-associated clinical clues suggesting secondary IGF-I deficiency such as optic nerve hypoplasia and skeletal abnormalities.

GH Mechanism of Action

Understanding of the mechanism of action of GH remains incomplete; however, it is known that, to initiate its growth-promoting and metabolic effects, it must bind to a transmembrane receptor that, unlike the insulin or IGF-I receptor, has no intrinsic kinase activity (Figure 1). Accordingly, it must recruit the cytoplasmic protein Janus kinase 2 (JAK2), which associates with and phosphorylates the GH receptor, providing a docking site for a cytosolic protein known as signal transducer and activator of transcription (STAT). Seven mammalian STATs have been identified and, although other STAT proteins may be involved, STAT5b is the critical STAT involved in GH regulation of IGF-I production.

Figure 1. Mechanisms of Growth Hormone (GH) Action GH stimulates a receptor, which activates signal transducer and activator of transcription (STAT), which subsequently translocates into the nucleus, activating transcription of insulin-like growth factor I (IGF-I) and a variety of other proteins. Source: Rosenfeld RG. Hormone Research. 2006; 65(suppl 1):15-20.

Genetic Defects of the GH/IGF-I Receptor Axis

Molecular defects of the GH/IGF-I axis can occur at multiple levels. Mutations or deletions in the GH gene itself or the GHR gene can occur.^2,3 In addition, mutations of the STAT5b gene and mutations or deletions of the IGF-I or the IGF-I receptor (IGF-IR) gene will result in some degree of growth failure.

GHR Mutation

Molecular defects of the GH/IGF-I axis can occur at multiple levels, such as mutation or deletion of the GH gene, the GHR gene, the STAT5b gene, or the IGF-IR gene. —Ron G. Rosenfeld, MD

To date, more than 300 cases of short stature with various mutations or deletions of the GHR gene have been identified. Most of the 60 distinct GHR gene mutations in the GH insensitivity syndrome (historically called Laron dwarfism or syndrome) are clustered in the region that encodes the extracellular domain, but occasionally there are mutations that affect the transmembrane or intracellular domain. Some of the recently identified GHR gene mutations are homozygous or compound heterozygous.⁴ Controversy persists regarding whether heterozygous mutations of the GHR gene can produce a clinical phenotype of short stature. Certain mutations can have phenotypic expression in the heterozygous state through a dominant negative effect, but whether that is true in the case of the GHR remains the subject of further investigation.

Children with GHR mutations are typically normal-sized at birth, suggesting that GH is likely to be of little significance in regulating intrauterine growth; however, affected patients have profound postnatal growth failure. GH levels are normal or often elevated, and may be dramatically so. Serum concentrations of GH binding protein, which is the circulating domain of the GHR, are usually low, especially when the mutation affects the extracellular domain. In rare mutations, however, levels can also be normal or elevated. Invariably, concentrations of IGF-I, insulin-like growth factor binding protein-3 (IGFBP-3), and acid-labile subunit (ALS) are low. Typically, serum levels of IGF-I will not rise when a patient is given GH as part of an IGF-I generation test.

STAT5b Mutations

STAT5b is the critical link between the GHR gene and the IGF-1 gene. It must be phosphorylated to serve this role. To date, there are 7 cases involving 6 mutations of the STAT5b agene resulting in severe GH insensitivity and IGF-I deficiency.

The phenotype of these patients is similar to that of patients with GHR gene mutations. For example, consider a 16-year-old female, from a consanguineous family who at first appeared to have classic Laron syndrome due to a defect in the GHR gene. Further analysis, however, demonstrated that her GHR gene was normal. She had an apparent deficiency of STAT5b, in particular phosphorylated STAT5b. Molecular analysis showed that she was homozygous for a point mutation resulting in a proline for alanine substitution at position 630 of the STAT5b gene. This position is near the tyrosine residue that must be phosphorylated. Further analysis demonstrated that, when given GH, she failed to phosphorylate her STAT5b and failed to transcriptionally activate IGF-I. Thus, even though STAT5b is produced, it is not functional because it cannot be phosphorylated and, consequently, the child is GH insensitive and IGF-I deficient.

Patients with genetic defects in STAT5b display normal size at birth, postnatal growth failure, and elevated GH.⁴ These patients have normal GH binding protein levels because the defect is not in the GH receptor. However, levels of IGF-I, IGFBP-3, and ALS are low and fail to rise when given GH during an IGF-I generation test. A unique similarity among these 7 patients was clinical evidence of immune dysfunction, with 5 having severe recurrent pulmonary disease. This can be explained by the fact that the GHR is a member of the cytokine receptor superfamily. Like many cytokine receptors, such as those activated by the interleukins, ?-interferons, and tumor necrosis factor, the GHR works through the JAK STAT system. Thus, STAT5b, in addition to being involved in GH action, is involved with cytokine action. This combination of severe growth failure, primary IGF-I deficiency, and immune dysfunction points toward STAT5b abnormalities.

IGF-I Gene Deletion

To date, only 1 case of an IGF-I gene deletion has been documented. This patient had a deletion of exon 4 of the IGF-I gene; accordingly, IGF-I levels were unmeasurable. As predicted by mouse knockout studies, and unlike patients with GHR and STAT defects, this patient had intrauterine growth retardation as well as postnatal growth failure.⁵ GH is relatively unimportant in intrauterine growth; however, IGF-I is important for normal growth to occur both pre- and postnatally.⁶ Since the report on this patient was published in 1996, several additional mutations have been identified. For example, the R36Q and V44M mutations result in a bioinactive IGF-I where the patient produces IGF-I, but the IGF-I is incapable of binding with or has very low affinity for the IGF-I receptor, and therefore is relatively bioinactive.⁷ In addition, a heterozygous splicing mutation was recently described, which affects the E domain of the IGF-I gene and protein, resulting in an abnormal IGF-I molecule being produced.

The phenotype of patients with genetic defects in IGF-I is characterized by intrauterine and postnatal growth failure, microcephaly, possible deafness, and developmental delay. Therefore, it seems likely that IGF-I in utero is involved with at least some development of the auditory and central nervous systems. GH levels are normal or increased in these patients, and GH binding protein is normal. Typically, IGF-I levels are low; in fact, they are below the limit of assay detection in patients with an IGF-I gene deletion. However, it is possible that IGF-1 levels can be normal or increased in patients with bioinactive IGF-I. Accordingly, the fact that the patient has a normal or even elevated serum level of IGF-I does not exclude the possibility of an IGF-I gene abnormality. Compensatory response by the pituitary to the low IGF-I levels results in production of additional GH, and serum levels of IGFBP-3 and ALS are normal or even increased in these patients.

ALS Gene Mutations

ALS is a carrier protein for IGF-I. It delivers IGF-1 to its receptor in the growth plates.⁸ To date, 20 patients have been identified with ALS gene mutations; accordingly, this abnormality is more common than initially suspected. Serum levels of ALS in patients with mutations in this gene are typically undetectable, accounting for the concomitant profoundly low serum levels of IGF-I and IGFBP-3. Surprisingly, these patients display relatively modest short stature. Because these patients have only modest growth failure with low IGF-I clevels, near -adequate levels of IGF-I are presumed to be available at the growth plate. In fact, some of these patients achieve a normal adult stature. Puberty may be delayed, however, and some patients may have low bone mineral density. Therefore, a combination of mild short stature and extremely low levels of IGF-I and IGFBP-3 may indicate ALS deficiency.

IGF-1R Gene Mutations

In order for IGF-I to exert its effects, it must bind to and activate its receptor. Thus, genetic abnormalities in the IGF-I receptor may also lead to growth defects. Patients with IGF receptor defects may have some degree of short stature. All patients reported thus far with short stature and IGF-IR gene mutations were heterozygotes, except for one patient who was a compound heterozygote with 2 mild mutations.⁴

The phenotype of these patients is characterized by intrauterine growth retardation combined with postnatal growth failure. This also supports a role of IGF-I in intrauterine growth. GH and GH binding protein levels are normal, IGF-I is normal or even increased, and IGFBP-3 and ALS levels are normal.

Therapeutic Considerations

GH treatment is typically the treatment of choice in GHD or secondary IGF-I deficiency. Conventionally, GH monotherapy is used in these patients.

IGF-I monotherapy is the treatment of choice for children with unequivocal GHR, STAT5b, or IGF-I gene defects. There is a paucity of clinical data, however, for patients with IGF-I receptor defects. These patients are heterozygotes or mild compound heterozygotes, or have deletions of 1 allele of the gene or at the end of chromosome 15 where the IGF-1R gene is located. It is possible that partial IGF resistance can be overcome with pharmacological dosages of GH or IGF-I, or by a combination of GH and IGF-I. It is not inconceivable that there may be additive or synergistic effects of GH and IGF-I in many of these disorders, and that more clinical data are needed.

Conclusion

The complexity of the genomics of growth disorders continues to unravel, and more research must be done to maintain progress that will benefit patients with these disorders. Specifically, the significance of heterozygous mutations must be investigated. More information must be acquired about the various polymorphisms of every component of the GH/IGF-I axis. Through dedicated research, this understanding is evolving as knowledge is gained about how genetic abnormalities can contribute to growth failure at both the pituitary and peripheral levels.

References

1. Rosenfeld RG. Insulin-like growth factors and the basis of growth. The New England Journal of Medicine. 2003 Dec 4;349(23):2184-6.
2. Benbassat CA, Eshed V, Kamjin M, Laron Z. Are adult patients with Laron syndrome osteopenic? A comparison between dual-energy X-ray absorptiometry and volumetric bone densities. The Journal of Clinical Endocrinology and Metabolism. 2003 Oct;88(10):4586-9.
3. Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, Abeysinghe S, Krawczak M, Cooper DN. Human Gene Mutation Database (HGMD): 2003 update. Human Mutation. 2003 Jun;21(6):577-81.
4. Rosenfeld RG, Hwa V. Genetic Diagnosis of Growth Failure. In: Weiss RE, Referoff S (eds). Genetic Diagnosis of Endocrine Disorders. In press.
5. Woods KA, Camacho-Hübner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. The New England Journal of Medicine. 1996 Oct 31;335(18):1363-7.
6. Rosenfeld RG. Insulin-like Growth Factors and the Basis of Growth. New England Journal of Medicine. 2003 Dec 4;349(23):2184-6.
7. Walenkamp MJ, Karperien M, Pereira AM, Hilhorst-Hofstee Y, van Doorn J, Chen JW, Mohan S, Denley A, Forbes B, van Duyvenvoorde HA, van Thiel SW, Sluimers CA, Bax JJ, de Laat JA, Breuning MB, Romijn JA, Wit JM. Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. The Journal of Clinical Endocrinology and Metabolism. 2005 May;90(5):2855-64. Epub 2005 Mar 15.
8. Heath KE, Argente J, Barrios V, Pozo J, Díaz-González F, Martos-Moreno GA, Caimari M, Gracia R, Campos-Barros A. Primary acid-labile subunit deficiency due to recessive IGFALS mutations results in postnatal growth deficit associated with low circulating insulin growth factor (IGF)-I, IGF binding protein-3 levels, and hyperinsulinemia. The Journal of Clinical Endocrinology and Metabolism. 2008 May;93(5):1616-24. Epub 2008 Feb 26.

New Paradigms for the Treatment of Growth Hormone Deficiency

Pinchas Cohen, MD

Because a growth disorder can be due to multiple causes, the origin of the growth defect must be ascertained so that the appropriate treatment can be implemented. This requires a successful diagnosis of the patient with a growth disorder.

Diagnosis of Short Stature

Three major tools can aid in the diagnosis of children with short stature (Figure 1).¹ First, if the height of the patient is less than -2 SD, then further investigation and consideration of therapy are warranted. Second, IGF-I levels, also using a cutoff of -2 SD, are useful screening tools. Insulin-like growth factor-I (IGF-I) levels are almost universally low in patients with growth hormone deficiency (GHD), and the majority of patients with non–growth hormone deficient short stature also have low IGF-1 levels, although they may not be as pronounced. Third, growth hormone (GH) stimulation tests, with a peak cutoff of 10 ng/mL are useful for determining whether a child is responsive to GH. These tools are collectively useful in diagnosing GHD.

Figure 1. Diagnosing the Child with Short Stature The height of the patient, analysis of insulin-like growth factor I, and growth hormone stimulation tests are collectively useful in diagnosing the child with short stature. Source: Cohen P. J Clin Endo Metab. 2006; 91:4235-4236. Copyright 2006, The Endocrine Society. Reprinted with permission.

Although GH stimulation tests have an important role in the clinical management of short stature, their results can be arbitrary. Absolute definitions of GHD, IGF-I deficiency, and idiopathic short stature do not exist. Precise age- and gender-dependent normal values have not been defined. Some propose that IGF-I levels and magnetic resonance imaging (MRI) can substitute for GH stimulation tests; this approach may overdiagnose GHD, expose patients to unnecessary MRIs, and does not allow concomitant testing of the hypothalamic-pituitary-adrenal axis (as can be accomplished with some secretagogues that stimulate both GH and cortisol). However, the majority of clinicians and opinion leaders still continue to use auxological, bone age, and GH stimulation tests, with a peak GH level of >10 ng/mL most often used to define normalcy.²

Height and growth are the result of the synergism between GH secretion and GH sensitivity. Patients with reduced production of GH may have increased sensitivity, whereas patients with severe GH insensitivity have ample GH that has little or no effect. Patients with idiopathic GHD may have a combination of defects involving GH secretion as well as GH action. A precise genomic and biochemical tool to adequately identify these problems is not yet available. With current capabilities, GH dose responses can be used to assess GH responsiveness and potential GH insensitivity in children who are diagnosed with GHD.

Patients with complete organic or severe GHD have a steep GH dose response curve, demonstrating remarkable growth velocity at low doses of GH.^3,4 In patients with mild GH insensitivity, which is encountered in certain cases of idiopathic short stature, growth velocity is more responsive to therapy, whereas patients with more severe forms of GH insensitivity experience only a modest response to GH monotherapy.

In patients with GHD, there is a dose response effect from 25 ?g/kg/d up to 100 ?g/kg/d.⁴ Within each dose, however, particularly the dose of 50 ?g/kg/d commonly used in the United States, variability in the growth response exists. For example, some patients gain only 0.5 SD over 2 years, and some more than 3 SD during the same time interval. A similar pattern occurs with the serum IGF-I response to GH treatment. Despite substantial dose responsiveness, there is much variability, and both the degree of dose response and the variability between the height and IGF-I responses is correlated.

In response to GH at the standard 50 ?g/kg/d and at the higher 100 ?g/kg/d doses, IGF serum levels increase above the upper limit of normal (ULN) in many patients. This is not known to be associated with short- or long-term side effects; however, it poses a theoretical concern (e.g., regarding the risk of certain cancers) that suggests it may be beneficial to avoid these abnormally high IGF-I levels.

Approach to the Patient with Short Stature

When performing a history and physical examination, clinicians should consider all causes of short stature.⁵ A careful assessment of auxological measurements including height and height velocity should be performed, followed by a series of tests for systemic and genetic diseases, including a karyotype to rule out Turner syndrome in short, slowly growing females regardless of the presence or absence of associated dysmorphic features. Tests for the diagnosis of certain genetic causes of short stature are now commercially available, which include pituitary transcription factor abnormalities.

If these initial diseases are excluded, additional tests for endocrine disease including bone age and thyroid testing should be performed, followed by static tests of the GH/IGF-I axis, including IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3). These are followed by dynamic tests for GH secretion, such as GH stimulation tests. The utility of dynamic tests for GH secretion, particularly the IGF-I generation test (in response to GH administration), may have benefit in selected cases. When GH secretion is of concern, a contrast-enhanced MRI of the pituitary should be performed to rule out structural problems in the hypothalamic pituitary regions. At this time, additional relevant genetic testing that was not done earlier should also be performed.

The integration of the information obtained, with the individual contributing data elements not necessarily being definitive, is used to make a final diagnosis and devise a treatment plan.

Treatment for Patients with GHD

While a variety of indications for GH therapy exist, the central one is GHD. Although GH is one of the safest pediatric medications available, common side effects include edema, joint pain, and bruising at the injection site. Rare side effects include slipped capital femoral epiphysies, gynecomastia, pseudotumor cerebri (benign intracranial hypertension), growth (without malignant transformation) of nevi, and worsening of existing scoliosis. Hyperinsulinemia, which is of unknown significance, has been observed as rare, reversible cases of type 2 diabetes mellitus.

A previously raised concern tht leukemia may be a side effect of GH therapy has been discounted. There is also no evidence that GH treatment causes specific advancement of bone age or puberty.

There are, however, concerns about adverse events of GH treatment in selected populations; for example, sleep apnea related to tonsillar hyperplasia in patients with Prader-Willi syndrome. There is also a concern that GH therapy might cause an exacerbation of insulin resistance in children who were born small-for-gestational-age. Critically ill adults in intensive care may have an increased risk of death on high doses of GH.⁶

There is some as yet unsubstantiated concern that long-term GH use may be associated with elevated risk for cancer. Active malignancy is a contraindication for GH therapy. In some patients with a previous malignancy that itself or its treatment caused GHD, a potential borderline increase in the incidence of second malignancies has been reported.⁷ This warrants careful monitoring and evaluation in larger cohorts.

IGF-I-based GH Dose Titration

Side effects of GH therapy may be either GH dose-dependent or serum IGF-I concentration dependent. A study of the National Health and Nutrition Examination Survey data revealed normal subjects with serum IGF-I levels below the 12th percentile or above the 88th percentile had an increased risk of overall mortality.⁸ Moreover, a separate study observed that serum levels of IGF-I measured in healthy individuals who participated in the Harvard Physicians’ Health Study appeared to be directly related to the risk for developing certain cancers 2 to 10 years later.⁹

IGF-I-based GH dose titration has become a central tenet of GH management in the United States over the last decade.¹⁰ Higher doses of GH result in augmented growth, but with a large scatter of individual serum IGF-I levels as well as auxological responses. Furthermore, 2 studies have shown that, at the highest approved GH dose of 100 ?g/kg/d (for GH-deficient children in puberty), IGF-I levels above the ULN occurred in at least one half of the patients.^4,11 IGF-I levels above the ULN were also induced in some patients with lower doses of GH. Theoretically, these extremely high IGF-I levels may represent a safety issue in terms of long-term complications. GH dose titration based on IGF-I levels is commonly used in adults with GHD; accordingly, it was assumed that this approach may lead to improved safety and efficacy in pediatric patients.

A randomized controlled study of the IGF-I-based strategy for optimizing GH treatment followed 170 naive (previously untreated) children with GHD or IGF-I deficiency (called, in this study, idiopathic short stature).¹⁰ Subjects were placed on GH therapy after being randomized to 1 of 3 groups: conventional dosing with GH at 40 ?g/kg/d (CONV); a variable GH dose targeting the IGF-I level to the mean (RCC1); or targeting the IGF-I level to the ULN (RCC2). Because of the study design, doses to the latter group could feasibly exceed the FDA-approved dose. Patients were followed for 2 years, with IGF-I levels measured at 3-month intervals with GH doses adjusted as warranted.

Targeting the IGF-I level to the ULN resulted in substantially more rapid, significant growth compared with that seen in the other 2 groups (Figure 2). A small, insignificant effect was achieved in the group with IGF-I levels targeted to the mean (RCC1) compared with those maintained on 40 ?g/kg/d (CONV). Paradoxically, the RCC1 group received approximately 10% less GH than did the CONV group.

Figure 2. Randomized Controlled Trial of IGF-I-Based Dosing Targeting the IGF-I levels to the upper limit of normal resulted in substantially more rapid, significant growth. Source: Cohen P et al. J Clin Endocrinol Metab . 2007;92: 2480–2486. Copyright 2007, The Endocrine Society. Reprinted with permission.

The dose of GH in the group of subjects whose IGF-I levels were targeted to the ULN (RCC2) was substantially larger than that of the other 2 groups. GH-deficient subjects required a dose of approximately 60 ?g/kg/d, whereas those with idiopathic short stature required more than 120 ?g/kg/d, which exceeds the labeled dose and would not be reasonable to use in a standard clinical care of a pediatric patient. Therefore, rather than titrate all patients to the ULN, IGF-I-based dosing should follow clinical judgment to attain the most reasonably useful dosage of GH for each patient. IGF-I sensitivity and the usefulness of IGF-I levels in individual patients can vary. Therefore, modulating this approach using growth velocity–based dosage can attain the best possible outcome for GH-treated patients.

Strategies for Managing GH Therapy

Because the response to GH treatment is variable, it is important to know the criteria to follow in making management decisions (Table 1). A recent consensus statement recommends that a successful first-year response to GH therapy should include an improvement in height SD score of at least 0.3 to 0.5 depending on the age of the patient, a height velocity increase of at least 3 cm, or a height velocity SD score of > 1.

Table 1. Strategies for Managing Growth Hormone Treatment Because the response to GH treatment is variable, it is important to be aware of the proper criteria to follow when making management decisions. Source: Pinchas Cohen, MD.

Growth velocity response curves based on prepubertal age and gender for specific diagnoses including idiopathic GHD, organic GHD, idiopathic short stature, and Turner syndrome are useful in identifying expected and inadequate growth velocity for these patient groups.¹² This can be used as a decision tool to increase the dose or modulate treatment.

At present, no other biochemical tests including hemoglobin A1C and CBCs are routinely recommended in GH-treated patients. Some authorities, however, suggest that thyroid hormone levels should be measured in some patients for the first few years after starting GH therapy.

To individualize and optimize the response to GH treatment, 3 dosing strategies can be followed. Weight-based dosing is used internationally in pediatric patients, although it has variability in absorption and responsiveness. With growth velocity or auxology-based dosing, higher GH doses are given to patients with poor response. Finally, many groups cnow advocate IGF-I-based GH dosing, where the dose of GH is titrated to achieve a desired IGF-I target expressed as a SD score for age and gender. In addition, it is generally accepted that serial IGF-I levels obtained during the course of GH therapy can be useful to assess safety and compliance, as well as serving as a tool for adjusting the GH dose.

Prediction models have been used primarily in Europe to help select GH starting doses.^13,14 Although the mean height outcome in a subpopulation of patients treated with this approach did not improve, variability was decreased and poor responders were identified a priori, allowing them to be treated from the beginning with higher doses of GH to achieve better growth. This tool should be combined with growth velocity and IGF-I-based dosing to assure optimal patient outcomes through state-of-the-art treatment.

The maximum recommended GH dosage for GH-deficient children is 35 ?g/kg/d to 50 ?g/kg/d in prepubertal children and up to 100 ?g/kg/d during puberty. In other indications for which GH is approved, such as patients with Turner syndrome, patients born small-for-gestational-age, and patients with idiopathic short stature, higher doses are frequently used, even in prepubertal patients. Starting at an intermediate dose within the approved range and adjusting the dose as necessary for each patient is common practice. After 2 years of treatment with GH, if the dose has been adjusted upwards to the limit of the approved dosage and the growth rate remains inadequate, then GH should be stopped and alternative therapy should be considered.¹⁵

Treating the High Risk-Patient with GH

In some patients it is prudent to focus primarily on safety rather than efficacy. For patients with previous malignancies, GHD should be a stringent diagnosis. To be prudent, despite true compelling evidence-based support, these patients should probably be treated with lower doses of GH and serum IGF-I levels should be monitored and maintained at or even slightly below the population mean. Risks should be discussed with the patient’s family.

In a recent consensus guideline statement regarding adult GHD, endorsed by the Growth Hormone Research Society, Lawson Wilkins Pediatric Endocrine Society, and other international bodies, patients with definite GHD resulting from genetic problems, surgery of the pituitary, or other organic causes, were not precluded from continuing GH therapy.¹⁶ GH treatment in these patients can be transitioned to adult protocols directly. In patients with idiopathic GHD, GH should be discontinued, and the patient should be retested according to adult protocols. If GH is continued, the dose should be decreased from the adolescent dosing protocol, which can reach 100 ?g/kg/d, to adult GHD strategies, which can be as low as 10 ?g/kg/d. Titration of the GH dose to achieve an IGF-I level that is age appropriate is recommended.

References

1. Cohen P. Controversy in clinical endocrinology: problems with reclassification of insulin-like growth factor I production and action disorders. The Journal of Clinical Endocrinology and Metabolism. 2006 Nov;91(11):4235-6. Epub 2006 Sep 5.
2. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, Chernausek SD, Savage MO, Wit JM; 2007 ISS Consensus Workshop participants. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. The Journal of Clinical Endocrinology and Metabolism. 2008 Nov;93(11):4210-7. Epub 2008 Sep 9.
3. Frasier SD, Costin G, Lippe BM, Aceto T Jr, Bunger PF. A dose-response curve for human growth hormone. The Journal of Clinical Endocrinology and Metabolism. 1981 Dec;53(6):1213-7.
4. Cohen P, Bright GM, Rogol AD, Kappelgaard AM, Rosenfeld RG; American Norditropin Clinical Trials Group. Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety. The Journal of Clinical Endocrinology and Metabolism. 2002 Jan;87(1):90-8.
5. Rosenfeld RG, Cohen P. Disorders of Growth Hormone/Insulin-Like Growth Factor Secretion and Action. In: Sperling, M ed. Pediatric Endocrinology. 3rd ed. Philadelphia: Saunders; 2008; 254-334.
6. Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ. Increased mortality associated with growth hormone treatment in critically ill adults. The New England Journal of Medicine. 1999 Sep 9;341(11):785-92.
7. Banerjee I, Clayton PE. Growth hormone treatment and cancer risk. Endocrinology and Metabolism Clinics of North America. 2007 Mar;36(1):247-63.
8. Saydah S, Graubard B, Ballard-Barbash R, Berrigan D. Insulin-like growth factors and subsequent risk of mortality in the United States. American Journal of Epidemiology. 2007 Sep 1;166(5):518-26. Epub 2007 Jun 29.
9. Giovannucci E, Pollak MN, Platz EA, Willett WC, Stampfer MJ, Majeed N, Colditz GA, Speizer FE, Hankinson SE. A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women. Cancer Epidemiology, Biomarkers & Prevention. 2000 Apr;9(4):345-9.
10. Cohen P, Rogol AD, Howard CP, Bright GM, Kappelgaard AM, Rosenfeld RG; American Norditropin Study Group. Insulin growth factor-based dosing of growth hormone therapy in children: a randomized, controlled study. The Journal of Clinical Endocrinology and Metabolism. 2007 Jul;92(7):2480-6. Epub 2007 Mar 13.
11. Mauras N, Attie KM, Reiter EO, Saenger P, Baptista J. High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative Study Group. The Journal of Clinical Endocrinology and Metabolism. 2000 Oct;85(10):3653-60.
12. Bakker B, Frane J, Anhalt H, Lippe B, Rosenfeld RG. Height velocity targets from the national cooperative growth study for first-year growth hormone responses in short children. The Journal of Clinical Endocrinology and Metabolism. 2008 Feb;93(2):352-7. Epub 2007 Nov 13.
13. Kriström B, Aronson AS, Dahlgren J, Gustafsson J, Halldin M, Ivarsson SA, Nilsson NO, Svensson J, Tuvemo T, Albertsson-Wikland K. Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature. The Journal of Clinical Endocrinology and Metabolism. 2009 Feb;94(2):483-90. Epub 2008 Nov 11.
14. de Ridder MA, Stijnen T, Hokken-Koelega AC. Validation and calibration of the Kabi Pharmacia International Growth Study prediction model for children with idiopathic growth hormone deficiency. The Journal of Clinical Endocrinology and Metabolism. 2003 Mar;88(3):1223-7.
15. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, Chernausek SD, Savage MO, Wit JM; 2007 ISS Consensus Workshop participants. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. The Journal of Clinical Endocrinology and Metabolism. 2008 Nov;93(11):4210-7. Epub 2008 Sep 9.
16. Ho KK; 2007 GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. European Journal of Endocrinology. 2007 Dec;157(6):695-700.

Discussion

The Laron series of patients with primary growth hormone resistance or insensitivity did not reach adult height when treated with insulin-like growth factor-I (IGF-I) without growth hormone. In addition, patients experienced side effects associated with IGF-I. What key lessons can be learned from these patients?

Ron G. Rosenfeld, MD: The FDA has approved the use of IGF-I in patients with severe primary IGF-I deficiency, which is defined as a height below -3 SD and IGF-I below -3 SD in patients with normal growth hormone and no evidence of another etiology for the growth failure. The long-term experience with IGF-I, however, is that, although these patients respond with fairly dramatic accelerated growth, the growth rates do not match the experience with growth hormone alone in children with severe growth hormone deficiency.

Several possibilities have been proposed that may explain this phenomenon, including failure to use optimum IGF-I doses, inadequate access of the exogenous IGF-I to its tissue receptor, insufficient serum concentrations of binding proteins to maximize IGF-I activity, or the possibility that growth hormone and IGF-I may have independent and overlapping effects. The latter consideration contributes to the justification for combination therapy.

In summary, although IGF-I therapy is available with clear indications for its use, more data are needed before its full potential can be achieved.

Mark A. Sperling, MD: Patients who have mutations in the growth hormone gene itself, who make an abnormal growth hormone, will appear to be like patients with a mild case of Laron syndrome because they will have low IGF-I and growth failure. These patients have bioinactive growth hormone but, depending on the antigen used to develop the radioimmunoassay, they can have high concentrations of growth hormone in the presence of this poor growth and low IGF-I. Accordingly, they may be misclassified, perhaps as having a growth hormone receptor mutation, when in fact the problem is one of the growth hormone gene itself producing an abnormal molecule that is immunologically reactive but biologically inactive. More work needs to be done in this area as well.

What lies ahead in the the treatment for growth disorders?

Sperling: Treatment strategies for growth disorders are evolving. Growth hormone therapy is increasingly based on additional physiologic parameters, such as IGF-I dose titration, as knowledge of the complexities and interactions that produce people of small stature expands. Moving forward, several advancements are envisioned that are logical extensions of the strategies summarized here. First, therapy with IGF-I has begun, and IGF-I/growth hormone in combination may be on the horizon. Long-acting growth hormone, which is expected to improve patient compliance and response, is under development, as are other forms of growth-promoting therapy such as oral growth hormone secretagogues. Aromatase inhibitors are used off-label on a widescale basis in the United States. The need to remain current in this exciting discipline is obvious, where the ability to achieve personalized medicine is rapidly approaching.