The primary treatment goals for patients diagnosed with acromegaly are to reduce GH and IGF-1 concentrations, improve the clinical signs and symptoms of the disease, and decrease mortality.7,8,11,12,13,14 Many clinicians define biochemical control of acromegaly as suppression of GH concentrations to less than 1 μg/L (less than 45 pmol/L) after a standard OGTT in the presence of normal IGF-1 serum concentrations, although some argue for a lower cutoff GH value of 0.4 μg/L (18 pmol/L) due to the availability of more sensitive test methods.13 The treatment of choice for most patients with acromegaly is transsphenoidal surgical resection of the GH-secreting adenoma (strong recommendation, moderate quality evidence).7,8,11,12,13 Postsurgical cure rates have been reported to range from 50% to 90%, depending on the type of adenoma and the expertise of the neurosurgeon.7,8,13,14 Complications of transsphenoidal surgery are relatively infrequent and include cerebrospinal fluid leak, meningitis, arachnoiditis, diabetes insipidus, and pituitary failure.8 For patients who are poor surgical candidates, those who have not responded to surgical or medical interventions, or others who refuse surgical or medical treatment, radiation therapy may be considered. Radiation, however, may require several years to relieve the symptoms of acromegaly.
Because neither radiation therapy nor surgery will cure all patients with acromegaly, adjuvant drug therapy is often needed to control symptoms.7,8,11,12
Drug therapy should be considered primary therapy for acromegalic patients who prefer medical therapy, are poor surgical candidates, or when there is a poor likelihood of surgical success. Drug therapy should be considered adjunctive therapy in the presence of persistent disease after surgery (strong recommendation, high quality evidence).7,8 Pharmacologic treatment options include dopamine agonists, somatostatin analogs, and the GH-receptor antagonist pegvisomant. Dopamine agonists such as bromocriptine and cabergoline are effective in a small subset of patients and provide the advantages of oral dosing and reduced cost. Somatostatin analogs are more effective than dopamine agonists, reducing GH concentrations and normalizing IGF-1 in approximately 50% to 60% of patients. Pegvisomant, a GH-receptor antagonist, is highly effective in normalizing IGF-1 concentrations in up to 97% of patients in the first year and in 60% over 5 years.
In normal healthy adults, dopamine agonists cause an increase in GH production. However, when these agents are given to patients with acromegaly, there is a paradoxical decrease in GH production. Most clinical experience with the use of dopamine agonists in acromegaly is with bromocriptine or cabergoline. Other agents such as pergolide, quinagolide, and lisuride also have been used but are not available in the United States. Bromocriptine and cabergoline are semisynthetic ergot alkaloids that act as dopamine-receptor agonists. Most trials assessing the efficacy of bromocriptine in the treatment of acromegaly were conducted in the 1970s and early 1980s and determined that bromocriptine was effective in suppressing mean serum GH levels to less than 5 μg/L (less than 225 pmol/L) in approximately 20% of patients.15 While only 10% of patients experience normalization of IGF-1 concentrations with bromocriptine therapy, more than 50% of patients treated with bromocriptine experience improvement in symptoms of acromegaly.8,15 According to AACE guidelines, cabergoline appears to be used more commonly than bromocriptine.8 A meta-analysis of 15 studies concluded that cabergoline as monotherapy was effective in normalizing IGF-1 levels in 34% of patients and resulted in normalization of IGF-1 levels in 52% of patients when added to a somatostatin analog in those unresponsive to somatostatin analog monotherapy.16
In the United States, bromocriptine is commercially available as 0.8 and 2.5-mg oral tablets and 5-mg oral capsules. The 0.8-mg tablet is only indicated for adjunctive therapy in type 2 diabetes mellitus. In acromegalic patients, significant reductions in GH concentrations are observed within 1 to 2 hours of oral dosing. This effect persists for at least 4 to 5 hours. An overall clinical response in acromegalic patients typically occurs after 4 to 8 weeks of continuous bromocriptine therapy. For treatment of acromegaly, bromocriptine is initiated at a dose of 1.25 mg (1/2 of a 2.5-mg tablet) at bedtime and is increased by 1.25-mg increments every 3 to 4 days as needed. Doses as high as 86 mg/day have been used for treatment of acromegaly, but clinical studies have shown that dosages more than 20 to 30 mg daily do not offer additional benefits in the suppression of GH. When used for treatment of acromegaly, the duration of action of bromocriptine is shorter than that for treatment of hyperprolactinemia. Therefore, the total daily dose of bromocriptine should be divided into three or four doses.
Cabergoline is commercially available as 0.5 mg tablets. Use in acromegaly is considered off-label, and dosing is typically initiated at 0.5 mg twice weekly and increased as needed to 0.5 mg every other day. Doses up to 7 mg/wk (0.5 mg twice daily) have been reported in trials.
The most common adverse effects of dopamine agonist therapy include central nervous system (CNS) symptoms such as headache, lightheadedness, dizziness, nervousness, and fatigue. Gastrointestinal (GI) effects such as nausea, abdominal pain, or diarrhea also are very common. Some patients may need to take dopamine agonists with food to decrease the incidence of adverse GI effects. Most adverse effects are seen early in the course of therapy and tend to decrease with continued treatment.8,15 Dopamine agonists may cause thickening of bronchial secretions and nasal congestion. Rare cases of psychiatric disturbances, pleural diseases, and an erythromelalgic syndrome (painful paroxysmal dilation of the blood vessels in the skin of the feet and lower extremities) have been reported with dopamine agonist use. These conditions appear to be associated with higher doses and prolonged duration of therapy.8,15
Dopamine agonists are not FDA-approved for use during pregnancy. However, surveillance of women who took dopamine agonists throughout pregnancy does not suggest that dopamine agonists are associated with an increased risk for birth defects.17 If a woman becomes pregnant while taking dopamine agonists, the risks and benefits of therapy should be fully considered. In most cases, the benefits of successful therapy outweigh the risks, and dopamine agonist therapy should be continued if it is effective in improving symptoms and reducing elevated GH concentrations.
Other dopamine agonists that have been used to treat acromegaly include pergolide, lisuride, and quinagolide. Pergolide is no longer commercially available, and lisuride and quinagolide are not commercially available in the United States. Because of the potential cost advantages and convenience of oral administration, dopamine agonists are often considered for treatment of acromegaly prior to initiation of somatostatin analogs. The Endocrine Society guidelines suggest a trial of a dopamine agonist in acromegalic patients with mild signs and symptoms and modest elevations in serum IGF-1.7 (weak recommendation, low quality evidence) However, the availability of long-acting somatostatin analogs has made these agents more attractive for first-line treatment of acromegaly.
Octreotide, lanreotide, and pasireotide are long-acting somatostatin analogs that are more potent in inhibiting GH secretion than endogenous somatostatin.18 The Endocrine Society suggests somatostatin analogs as initial adjuvant medical therapy in patients with significant disease (weak recommendation, low quality evidence) and as primary therapy in patients who cannot be cured by surgery or are poor surgical candidates.7 (weak recommendation, moderate quality evidence). These agents also suppress the LH response to GnRH; decrease splanchnic blood flow; and inhibit secretion of insulin, vasoactive intestinal peptide (VIP), gastrin, secretin, motilin, serotonin, and pancreatic polypeptide. Pasireotide is a somatostatin analog that has a broader affinity for somatostatin receptor subtypes than octreotide or lanreotide. The binding to additional subtypes of somatostatin receptors may result in greater GH inhibition compared to octreotide or lanreotide and efficacy of pasireotide in the presence of octreotide or lanreotide-resistant adenomas.18
Octreotide (Sandostatin) injection is commercially available in the United States for subcutaneous or IV administration. A long-acting intramuscular formulation of octreotide (Sandostatin LAR) is available for monthly administration. An investigational oral formulation of octreotide administered as monotherapy was effective in maintaining control of IGF-1 and GH serum concentrations in patients previously well controlled with an injectable formulation.19 In addition to the treatment of acromegaly, octreotide has many other therapeutic uses, including the treatment of carcinoid tumors, vasoactive intestinal peptide-secreting tumors (VIPomas), GI fistulas, variceal bleeding, diarrheal states, and irritable bowel syndrome.
The efficacy of octreotide for treatment of acromegaly was initially determined by two major multicenter trials.20,21 These studies demonstrated that drug therapy with octreotide suppresses mean serum GH concentrations to less than 5 μg/L (less than 225 pmol/L) and normalizes serum IGF-1 concentrations in 50% to 60% of acromegalic patients and reduces the clinical signs and symptoms of acromegaly. In a 6-month multicenter trial, 70% of patients experienced significant relief of headaches.21 In some patients, relief of headache symptoms occurred within minutes of octreotide administration. In addition, middle-finger circumference was reduced significantly, and 50% to 75% of patients experienced improvement in symptoms of excessive perspiration, fatigue, joint pain, and cystic acne. Long-term follow-up of patients treated with octreotide LAR for up to 9 years showed octreotide therapy to be safe and effective for long-term use in acromegalic patients.22 Octreotide also has been shown to improve the cardiovascular manifestations of acromegaly and to halt pituitary tumor growth, with some patients experiencing tumor regression.23 Data from more recent studies indicate that shrinkage of pituitary tumor mass during octreotide therapy occurs in approximately 50% of patients.24
The pharmacodynamic effects of long-acting octreotide are similar to those of subcutaneously administered octreotide. Single monthly doses of long-acting octreotide have been shown to be at least as effective as daily doses of subcutaneous octreotide administered in divided doses three times daily in normalizing IGF-1 levels and maintaining suppression of mean serum GH concentrations.25 Trials evaluating the efficacy of long-acting octreotide in acromegalic patients who previously had responded to subcutaneously administered octreotide have reported sustained suppression of GH concentrations to less than 5 μg/L (less than 225 pmol/L) and normalization of IGF-1 in patients following 1 year of therapy.25
Response to long-term therapy with octreotide is related to the presence and increased quantity of functioning somatostatin receptors located in the pituitary adenoma. Identification of patients who most likely will respond to octreotide, prior to initiation of therapy, is important when considering the high cost of this medication and the inconvenience of subcutaneous or intramuscular drug administration. Suppression of serum GH concentrations after a single 50-μg dose of octreotide has been used to predict a favorable long-term response to octreotide therapy but reliability of this test is not universally accepted.7,26
The initial dose of octreotide for treatment of acromegaly is usually 100 μg administered three times daily followed by either titration to a maximum of 1,500 μg/day or transition to long-acting octreotide.8 Some clinicians recommend a starting dose of 50 μg every 8 hours, then increasing the dose to 100 μg every 8 hours after 1 week, to improve the patient’s tolerance of adverse GI effects. The dose can be increased by increments of 50 μg every 1 to 2 weeks based on mean serum GH and IGF-1 concentrations. Patients who experience a significant rise in GH prior to the end of the 8-hour dosing interval may benefit from decreasing the dosing interval to every 4 to 6 hours. Although doses as high as 1,500 μg/day have been used, doses greater than 600 μg daily generally do not offer additional benefits, and most patients are adequately managed with 100 to 200 μg three times daily.8 Patients who have been maintained on subcutaneous octreotide for at least 2 weeks and have shown response to therapy can be converted to the long-acting depot form of octreotide. The initial dose of long-acting octreotide is 20 mg administered intramuscularly in the gluteal region every 28 days. Steady-state serum concentrations are not obtained until after 3 months of therapy. Therefore, dosage adjustments for long-acting octreotide should not be considered until after this time. Some patients may require additional subcutaneous injections during the initial dose-titration phase in order to control symptoms. In patients who achieve more than 50% reduction in GH levels to 30 mg every 4 weeks, some may have added response to a higher-dose regimen of 60 mg every 4 weeks.27
Lanreotide (Somatuline Depot) is commercially available in the United States for monthly, deep subcutaneous administration. In addition to acromegaly, lanreotide is also indicated for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The efficacy of this preparation of lanreotide for the treatment of acromegaly has been evaluated in several prospective multicenter clinical trials involving treatment-naïve and treatment-experienced patients who were switched from intramuscular octreotide LAR or intramuscular lanreotide LA to monthly deep subcutaneous lanreotide.28 These studies have determined that deep subcutaneous lanreotide suppresses mean serum GH concentrations to less than 5 μg/L (less than 225 pmol/L) and normalizes serum IGF-1 concentrations in acromegalic patients to a similar extent as octreotide LAR and lanreotide LA. A 4-year follow-up of 23 patients treated with monthly deep subcutaneous lanreotide reported the drug to be well tolerated during long-term therapy with mean serum GH concentrations less than 5 μg/L (less than 225 pmol/L) in 62% of patients and normalization of serum IGF-1 concentrations in 43% of patients.29 Analyses of trials investigating the effects of lanreotide on pituitary tumor mass have shown shrinkage in the majority of patients, and the response appears to be more prevalent in treatment-naïve patients and in patients with macroadenomas.28,30 Well-designed trials directly comparing the efficacy of intramuscular octreotide LAR to deep subcutaneous lanreotide are currently lacking. However, these two agents are generally regarded to have comparable efficacy.7,8 Lanreotide (Somatuline Depot) is commercially available in the United States as 60-, 90-, and 120-mg prefilled syringes. In contrast to octreotide LAR and pasireotide, lanreotide injection does not need to be reconstituted prior to administration. The initial recommended dose of lanreotide is 90 mg given by deep subcutaneous injection in the superior external quadrant of the buttock every 28 days. Injection sites should be alternated between the left and right side. The initial dose should be reduced to 60 mg every 28 days for patients with moderate or severe renal or hepatic impairment. After 3 months of therapy, the dose may then be titrated based on serum GH concentrations, serum IGF-1 concentrations, and control of clinical signs and symptoms of acromegaly.28 Long-acting deep subcutaneous lanreotide injection in doses more than 120 mg every 28 days has not been studied. Extended dosing intervals of up to every 8 weeks are currently under investigation.31
Pasireotide (Signifor LAR) for the treatment of acromegaly is commercially available in the United States in the form of a monthly intramuscular injection. Another formulation of pasireotide (Signifor) is approved for treatment of Cushing disease as a twice daily subcutaneous injection. The efficacy of the long-acting pasireotide formulation has been evaluated in both drug-naïve patients and those inadequately controlled on long-acting octreotide or lanreotide.32,33,34,35 In drug-naïve acromegalic patients, drug therapy over 12 months with pasireotide suppressed mean serum GH concentrations to less than 2.5 μg/L and normalized serum IGF-1 concentrations in 38% compared to 23% with octreotide.33 An extension study of up to 25 months noted long-term biochemical control (GH less than 2.5 μg/L and normal IGF-1) in 48% with pasireotide compared with 45% with octreotide.34 In patients inadequately controlled with octreotide or lanreotide, drug therapy with pasireotide over a 24-week period resulted in biochemical control (GH less than 2.5 μg/L and normal IGF-1) in 15% to 20% of patients.35
The initial recommended dose of pasireotide is 40 mg given by intramuscular injection every 28 days. The initial dose should be reduced to 20 mg every 28 days for patients with moderate or severe hepatic impairment. After 3 months of therapy, the dose may be titrated based on serum GH concentrations, serum IGF-1 concentrations, and control of clinical signs and symptoms of acromegaly. Doses of pasireotide exceeding 60 mg every 28 days are not recommended.32 The most common adverse effects of somatostatin analog therapy are GI disturbances such as diarrhea, nausea, abdominal cramps, malabsorption of fat, and flatulence.25,28,32 GI adverse effects occur in approximately 75% of patients but usually subside within 10 to 14 days of continued treatment. Octreotide has been reported to cause injection-site pain (4%-31%), conduction abnormalities and arrhythmias (9%), subclinical hypothyroidism (2%-12%), biliary tract disorders (4%-50%), and abnormalities in glucose metabolism (2%-18%). Lanreotide has been reported to cause injection-site reactions (9%), sinus bradycardia (3%), hypertension (5%), biliary tract disorders (20%), and abnormalities in glucose metabolism (7%). The incidence of adverse effects with pasireotide is similar to octreotide and lanreotide with the exception of a higher incidence of hyperglycemia (61%-67% vs 25%-30%) often requiring treatment with antidiabetes medications (38%-39% vs 6%).
Somatostatin analogs also inhibit cholecystokinin release and gallbladder motility, predisposing patients to the development of cholelithiasis.36 The development of gallstones is a long-term adverse effect of somatostatin analog therapy and is largely dependent on geographic factors, dietary habits, and length of therapy. The incidence of gallstones in acromegalic patients receiving octreotide and lanreotide increases with length of therapy and has been reported to range from 20% to 50%.25,28,32 However, most patients are asymptomatic, and the diagnosis of cholelithiasis usually is made following an ultrasonographic study that is not prompted by patient symptoms. It has been estimated that only 1% of patients will develop symptomatic gallstones during 1 year of octreotide treatment.36 Because somatostatin analog-induced gallstones usually are present without clinical symptoms, prophylactic cholecystectomy or medical therapy with ursodeoxycholic acid for acromegalic patients with asymptomatic gallstones usually is not recommended. A small number of studies have suggested that the incidence of gallstone development may be lower with long-acting octreotide compared to subcutaneous octreotide.25 However, further studies are needed to confirm this observation.
The effect of somatostatin analogs on glucose metabolism in patients with acromegaly is multifactorial. Decreases in serum GH concentrations induced by somatostatin analogs should result in decreased hepatic gluconeogenesis and increased insulin-receptor sensitivity. However, somatostatin analogs also decrease insulin secretion and increase IGFBP-1, which is known to inhibit the insulin-like effects of IGF-1. In addition, somatostatin analogs delay the GI absorption of glucose, which may further alter glucose metabolism in acromegalic patients.38 Small studies conducted in acromegalic patients receiving octreotide have reported improvement in insulin sensitivity as well as impaired insulin secretion.39 Risk factors associated with worsening glucose tolerance included female sex and elevated baseline insulin values. Although somatostatin analogs appear to have a beneficial effect on glucose tolerance in most patients, glucose determinations should be obtained frequently in the early stages of therapy in all acromegalic patients.
Growth Hormone Receptor Antagonist
Pegvisomant (Somavert) is a genetically engineered GH derivative that binds to, but does not activate, GH receptors and inhibits IGF-1 production. This agent is different from other medications used in the management of acromegaly because it does not inhibit GH production; rather, it blocks the physiologic effects of GH on target tissues. Therefore, GH concentrations remain elevated during therapy, and response to treatment is evidenced by a reduction in IGF-1 concentrations. Unlike somatostatin analogs, the pharmacologic activity of pegvisomant does not depend on the presence and quantity of somatostatin receptors in the pituitary tumor.40 Studies evaluating the clinical efficacy of pegvisomant in acromegalic patients have reported a dose-dependent normalization of IGF-1 concentrations in 54% to 89% of patients after 12 weeks of therapy and in 97% of patients after 1 year of therapy.40,41 Significant improvements in the clinical signs and symptoms of acromegaly were reported and persisted throughout the 1-year treatment period.41 An ongoing, international postmarketing surveillance registry (ACROSTUDY) reported normalization of IGF-1 serum concentrations in 63% of patients treated with pegvisomant over 5 years of therapy. Investigators note that failure to maintain IGF-1 normalization may reflect suboptimal dosing strategies or more advanced disease than reported in the original studies.42
Adverse effects include injection-site pain, GI complaints such as nausea and diarrhea, and flu-like symptoms. Significant elevations in hepatic aminotransferase concentrations, which are generally reversible upon discontinuation of the drug, have been reported.43 As a result, hepatic function tests should be monitored very closely during therapy as outlined in the product labeling, and the drug should be used with caution in patients with baseline elevations in hepatic aminotransferase concentrations. GH concentrations may increase significantly during the first 6 months of therapy. Tumor growth has been reported in a small number of patients and there are theoretical concerns that the lack of GH feedback regulation on tumors that lead to persistently elevated GH concentrations may stimulate tumor growth or result in other long-term adverse effects. Results of the ongoing ACROSTUDY suggest that the rate of tumor growth of 3.2% is comparable to the background rate in acromegaly, and the incidence of hepatic aminotransferases greater than three times upper limit of normal is low (2.5%).42
Pegvisomant is commercially available in the United States for daily subcutaneous use. The first dose should be administered under the supervision of a physician as a 40-mg loading dose. Subsequent doses are self-administered by the patient starting at a dose of 10 mg daily. The dose can be adjusted in 5-mg increments based on serum IGF-1 concentrations every 4 to 6 weeks.43
Based on the available data, pegvisomant appears to be among the most effective agents for normalizing IGF-1 serum concentrations. Current guidelines for acromegaly management suggest pegvisomant therapy for patients who have failed to achieve normalization of IGF-1 serum concentrations with other treatments or as the initial adjuvant medical therapy.7,8,11
Several small studies have suggested that combination therapy with somatostatin analogs, dopamine agonists, or pegvisomant may be more beneficial than monotherapy with either drug alone.7,8 Several of these trials have used doses lower than those typically used for monotherapy in order to try to minimize the risk of additive adverse effects. The Endocrine Society recommends the addition of pegvisomant or cabergoline in patients with inadequate response to a somatostatin analog.7 (weak recommendation, low quality of evidence) Because of the potential for additive adverse effects, combination therapy should be considered as a therapeutic option only for refractory patients who have not fully responded to monotherapy.7,8
While several biomarkers have been studied in pituitary tumors, the prognostic value of these in predicting response to therapy is still unclear.44 The genetics of GH and its receptors have been well-studied.45 At this time, the data are most abundant with pegvisomant. As pegvisomant acts at the GH receptor, researchers have investigated response to GH receptor variants. In patients with exon 3-deleted GH receptors, lower doses and fewer months were needed to obtain IGF-1 normalization.46 However, recommendations regarding how therapy can be individualized to maximize patient benefit are not yet available.7,8,46
Some clinicians advocate the use of somatostatin analogs prior to surgery in order to improve comorbidities that may complicate surgery. However, sufficient evidence is lacking.47
Acromegaly is a chronic debilitating disease characterized by excess GH secretion most commonly caused by a GH-secreting pituitary adenoma. Transsphenoidal surgical resection of the adenoma is the current treatment of choice for most patients with acromegaly. Patients who are poor surgical candidates may receive radiation therapy or long-term pharmacologic therapy. Drug therapy options within the United States for acromegaly include dopamine agonists, somatostatin analogs, and pegvisomant. Figure e77-2 shows a treatment algorithm for the management of acromegaly.7,8
Treatment algorithm for acromegaly. (DA, dopamine agonist; MRI, magnetic resonance imaging; OGTT, oral glucose tolerance test; SRL, somatostatin analog; SRT, stereotactic radiotherapy.) (Modified from Katznelson L, Laws ER, Melmed S, et al. Acromegaly: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2014;99:3933-3951. Copyright 2014, The Endocrine Society.)
Growth Hormone Deficiency
Short stature is a condition that is commonly defined by a physical height that is more than two standard deviations below the population mean and lower than the third percentile for height in a specific age group.48 It has been estimated that more than 1.8 million children in the United States can be characterized as having short stature.48 Short stature is a very broad term describing a condition that may be the result of many different causes. A true lack of GH is among the least common causes and is known as GHD short stature. Absolute GH deficiency is a congenital disorder that can result from various genetic abnormalities, such as GHRH deficiency, GH gene deletion, and developmental disorders including pituitary aplasia or hypoplasia.48 GH insufficiency is an acquired condition that can result from hypothalamic or pituitary tumors (or their neurosurgical treatment), cranial irradiation, head trauma, pituitary infarction, and various types of CNS infections. In addition, psychosocial deprivation, hypothyroidism, poorly controlled diabetes mellitus, treatment of precocious puberty with LH-releasing hormone agonists, and pharmacologic agents such as glucocorticoids, methylphenidate, and dextroamphetamine may induce transient GH insufficiency.48
Short stature also occurs with several conditions that are not associated with a true GH deficiency or insufficiency. These conditions include intrauterine growth restriction; constitutional growth delay; malnutrition; malabsorption of nutrients associated with inflammatory bowel disease, celiac disease, and cystic fibrosis; chronic renal failure; skeletal and cartilage dysplasia; and genetic syndromes such as Turner syndrome.48,49 In addition, many children are diagnosed with idiopathic or normal variant short stature. These patients have heights that are significantly lower than the third percentile but present with normal GH serum concentrations and no specific underlying explanation for short stature.49
Children with congenital GHD usually are born with an average birth weight. Decreases in growth velocity generally become evident between the ages of 6 months and 3 years.48 In contrast, GH insufficiency may arise at any age during growth and development. The clinical characteristics of GHD or GH-insufficient children are listed in Table e77-3.48
TABLE e77-3Clinical Presentation of Short Stature |Favorite Table|Download (.pdf) TABLE e77-3 Clinical Presentation of Short Stature
The patient will present with reduced growth velocity and delayed skeletal maturation.
Children with GH-deficient or GH-insufficient short stature may also present with central obesity, prominence of the forehead, and immaturity of the face.
The patient will exhibit a peak GH concentration <10 μg/L (<450 pmol/L) following a GH provocation test. Reduced IGF-1 and concentrations may be present.
Because GH deficiency may be accompanied by loss of other pituitary hormones, hypoglycemia, and hypothyroidism may be noted.
Several factors must be considered in the diagnosis of GH deficiency or insufficiency. Standard epidemiologic growth charts developed by the National Center for Health Statistics typically are used to determine the percentile of anthropometric measurements, such as height, weight, and head circumference. Pubertal stage typically is determined using the Tanner method. Bone age is determined according to published standards, and growth velocity is calculated to determine the patient’s height velocity percentile using standard growth-velocity charts.48,49 GH deficiency is rarely seen in the absence of delayed skeletal maturation and decreased growth velocity. In addition, several different provocative stimuli that induce GH secretion may be used diagnostically to determine GH status. Common provocative pharmacologic GH stimuli include insulin-induced hypoglycemia, clonidine, L-dopa, arginine, glucagon, and GHRH.48 Traditionally, a subnormal GH response during childhood is arbitrarily defined as a peak GH serum concentration less than 10 μg/L (less than 450 pmol/L) during a 2-hour period after administration of one of these agents.48 However, a lower cutoff may be used for the peak GH response, depending on the specific assay and GH reference product used. For prepubertal and early pubertal patients (Tanner stage less than III), priming with sex hormones to improve the specificity of GH provocation tests is often considered. Some patients exhibit clinical signs of GH deficiency, subnormal growth velocity, and delayed bone age despite GH levels that are within normal limits after provocative testing. This makes diagnosis in this group of patients very difficult. Diagnosis based on GH stimulation tests becomes further complicated because of the paucity of data reporting the normal range of GH concentrations after provocative testing in healthy children and the fact that commercial GH and IGF-1 assays currently available may not be equivalent. Although a gold standard for diagnosis of GHD does not exist, treatment is generally recommended for children who have “idiopathic short stature” and pass GH provocative testing but have most of the following criteria: height greater than 2.25 standard deviations below the mean for age; subnormal growth velocity; delayed bone age; low serum IGF-1 and/or IGFBP-3; and other clinical features consistent with GH deficiency.50 Ultimately, careful consideration of multiple factors by a pediatric endocrinology specialist is required to correctly diagnose GH deficiency. Of note, more than half of children diagnosed with GH deficiency are found to secrete normal quantities of GH and IGF-1 in adulthood.51
The treatment of GH deficiency with pituitary-derived human GH was first reported in the late 1950s. The National Hormone and Pituitary Program was founded by the National Institutes of Health in 1963 to coordinate the collection of human pituitary glands and purification of GH for administration to children with GH deficiency. In 1985, three deaths linked to Creutzfeldt–Jakob disease (CJD) were identified in young individuals who were previously treated with human pituitary GH. An evaluation of National Hormone and Pituitary Program data identified 26 cases of fatal CJD in a cohort of 6,107 patients who received treatment with human pituitary-derived GH in the United States between 1963 and 1985.52 Cadaveric pituitary GH was withdrawn from the US market because of the strong likelihood that CJD was transmitted through contaminated human pituitary-derived hormone. Shortly after the withdrawal of human pituitary GH, the FDA approved the first recombinant DNA-derived GH for treatment of GH insufficiency. Prior to the introduction of recombinant GH, the number of individuals who received treatment for GH insufficiency was relatively small because of the limited availability of human pituitary tissue for GH extraction. Currently, with the widespread availability of recombinant GH products, a large number of children can receive GH replacement therapy at higher doses.
Many pediatric endocrinologists in the United States believe that GH therapy is appropriate treatment in certain patients with non-GHD short stature. However, given the high cost of therapy and small increases in height, use of GH in this patient population remains controversial.
Recombinant Growth Hormone
Recombinant GH is currently considered the mainstay of therapy for treatment of GHD short stature. GH replacement therapy in children with documented GHD short stature produces a significant improvement in growth velocity within the first year of therapy and significantly improves final adult height.53,54 The initial increase in growth velocity often is referred to as catch-up growth. Most of the initial studies evaluating the efficacy of GH therapy in GHD children were conducted for short periods of time in small numbers of patients and information about the long-term outcome of GH therapy was limited. Initial data suggested that final adult height is not substantially improved, with an average final adult height reported to be two standard deviations below the population mean.55,56 Although these results were disappointing, it is important to note that a substantial percentage of patients included in these studies initially had received human pituitary GH in relatively low doses because of its limited availability. In addition, current GH dosing regimens with regard to frequency of administration have changed, making these data difficult to interpret and apply to the patients who are receiving GH replacement therapy today. Recent studies evaluating the adult height of children who received only recombinant GH therapy with currently recommended dosing regimens suggest that current recombinant GH therapy has a greater impact on final adult height than previously reported.54,55,56 These studies have reported average final adult heights ranging from 0.5 to 1.7 standard deviations below the population mean. Initiation of therapy at an early chronologic age, prior to the onset of puberty, is associated with a more favorable increase in final height.48,53,54,55,56 Therefore, prompt diagnosis of GH deficiency and early initiation of replacement therapy with recombinant GH are crucial factors in optimizing the final adult height of children with GH deficiency.
Recombinant GH has been shown to increase the short-term growth rate in pediatric patients with chronic renal insufficiency, Turner syndrome, idiopathic short stature, Prader–Willi syndrome, short stature homeobox gene (SHOX) deficiency, Noonan syndrome, and children born small for gestational age (SGA), and is approved by the FDA for treatment of growth failure associated with these conditions. GH is also FDA-approved for treatment of adult GH deficiency, short bowel syndrome in patients receiving specialized nutritional support, and acquired immunodeficiency syndrome wasting syndrome. When used in adult patients, the recommended dosage of recombinant GH is significantly lower than the dosage used in pediatric patients. Adult patients with GH deficiency during childhood must have the diagnosis of GHD confirmed when they are adults. Long-term GH therapy in GHD adults significantly decreases body fat, increases muscle mass, and improves exercise capacity.51 GH therapy in adults has not been definitively shown to improve the cardiac risk profile or bone mineral density, but it does appear to improve psychological well-being.57 The Beers Criteria of the American Geriatrics Society recommends avoiding GH therapy except as replacement after pituitary gland removal because the risks in older adults outweigh any potential benefits.58 Use of GH as an anabolic agent for management of acute catabolism is not recommended.48
The majority of short children in the United States do not have an identifiable medical cause for their condition, but with widespread availability of several recombinant GH formulations, many children have received GH therapy regardless of the underlying etiology of their short stature. The use of recombinant GH therapy in children with non-GHD short stature, also referred to as idiopathic short stature, has been studied by many investigators and was approved by the FDA in 2003.49 However, the use of GH therapy in this patient population remains controversial.59,60 A meta-analysis of 38 clinical studies evaluating the efficacy of GH treatment in children with idiopathic short stature reported average increases in final adult height of 4 to 5 cm (1.6-2 inches) following a mean duration of therapy of 4.7 years.61 This corresponded to an increase above the predicted final adult height of 0.56 to 0.63 standard deviations of the population mean. A more recent systematic review of GH treatment in idiopathic short stature noted that the final adult height gain is usually less than that seen in other FDA-approved conditions associated with growth failure, increasing adult height by about 4 cm. The individual response to therapy is highly variable, and further studies are needed to identify responders.62
Nine different recombinant GH products (somatropin) currently are available for use in the United States (Genotropin, Humatrope, Norditropin, Nutropin AQ, Omnitrope, Saizen, Serostim, Zomactin, and Zorbtive). Somatropin is composed of the same amino acid sequence as native human pituitary GH. Recombinant GH formulations must be administered by intramuscular or subcutaneous injection. Nutropin AQ, Norditropin, and Omnitrope are the only GH products available as liquid formulations. The remaining products are formulated as lyophilized powders for injection, and patients must be instructed regarding proper administration. A needle-free injection device (Zoma-Jet) is available for use with Zomactin. This device delivers a thin stream of recombinant GH that penetrates the stratum corneum and deposits into the subcutaneous tissue. This product may be particularly useful for patients who experience significant adverse effects from injections. The potency of GH products is expressed as international units per milligram (international units/mg), with 1 mg containing approximately 2.6 international units of GH. Direct comparisons between the different recombinant GH products have not been published. However, all GH products are generally considered to be equally effective and some retrospective data suggest that switching formulations during the course of treatment may not negatively impact the growth trajectory.63 The recommended dose for treatment of GHD short stature in children ranges from 0.2 to 0.375 mg/kg/wk.48,52 Recombinant GH can be administered daily or in equal doses six times per week, depending on the specific GH product used.48,52 Dosing regimens with greater frequency of administration have been shown to provide more favorable short-term growth responses.48,52 While fixed-dose strategies have historically been used, most endocrinologists suggest that adjustments in GH replacement can be made based on IGF-1 serum concentrations as appropriate for age and sex.64,65 GH replacement therapy should be initiated as early as possible after diagnosis of GH insufficiency and continued until a desirable height is reached or growth velocity has decreased to less than 2.5 cm per year after the pubertal growth spurt. However, the suitable time point for discontinuation of therapy with growth-promoting doses remains controversial. Glucocorticoids may inhibit the growth-promoting effects of recombinant GH, and concomitant administration of androgens, estrogens, thyroid hormones, or anabolic steroids may accelerate epiphyseal closure and compromise final height.
Large databases, such as the National Cooperative Growth Study, the Kabi International Growth Study, and the Australian and New Zealand growth database (OZGROW), have been developed to collect postmarketing adverse event data associated with recombinant GH. Development of these databases was prompted by the unexpected and tragic cases of CJD reported in patients treated with human pituitary GH. These databases are organized and maintained by pharmaceutical companies that manufacture GH products.66,67,68 Results from the Safety and Appropriateness of Growth Hormone treatments in Europe (SAGhE) study provide additional long-term surveillance data from a noncommercial source.68 Recombinant GH is generally well tolerated in children, and adverse effects are relatively uncommon.66,67,68,69 A small number of patients may complain of injection-site pain or arthralgias. Idiopathic intracranial hypertension, also known as pseudotumor cerebri, has been reported in a very small number of children receiving GH therapy. This condition usually develops within the first 8 to 12 of weeks of treatment and presents with symptoms such as headache, blurred vision, diplopia, nausea, and vomiting.69 The symptoms of idiopathic intracranial hypertension usually resolve after discontinuation of GH therapy, and long-term complications are rare. Cases of slipped capital femoral epiphysis have been reported in children with GHD who are receiving GH therapy.68,69 This condition is thought to occur as a result of the increased width of the femoral plate during GH treatment, but it also has been reported in GHD children who are not receiving GH replacement. Patients with this condition typically complain of hip or knee pain. Slipped capital femoral epiphysis can be managed by an orthopedic surgeon, and GH therapy does not need to be withdrawn. Because GH is known to cause decreased insulin sensitivity, hyperglycemia and diabetes mellitus may develop.69 Patients who have specific predisposing risk factors for diabetes mellitus are at greatest risk for this adverse effect.66,69 Glycosylated hemoglobin concentrations should be monitored in all patients receiving GH products.48 GH could theoretically promote the growth of various types of neoplasms and increase tumor recurrence rates in patients with a history of malignancy.48,66,69 Guidelines recommend that GH can be safely used in those without a history of malignancy but note that current evidence is insufficient to conclude whether GH increases cancer risk or recurrence.70 In 1988, a Japanese report indicated that children receiving GH therapy were twice as likely to develop leukemia as children who were not receiving the hormone. A more recent analysis of all collected reports of leukemia associated with GH therapy determined that these children had other leukemia risk factors (Fanconi anemia, Bloom syndrome, or history of cancer).68 GH therapy in children without these risk factors does not appear to predispose children to develop leukemia.68,70 Concerns have been raised from the SAGhE cohort about the possibility that childhood GH exposure may be associated with diseases that may not manifest until adulthood. Increased cardiac and cerebrovascular mortality rates were observed in adult French subjects treated with GH therapy as children but similar results were not seen in subjects from Belgium, the Netherlands, and Sweden.68,71 The observational design of these studies makes interpretation of the findings difficult. Additionally, it should be noted that some authors have stressed the importance of using growth velocity and provocative testing in deciding whom and when to treat, and at what doses.
Recombinant Insulin-Like Growth Factor-1
Recombinant IGF-1 (mecasermin [Increlex]) is approved by the FDA for the treatment of children with short stature due to severe primary IGF-1 deficiency (defined as children with height standard deviation score ≤–3.0 plus basal IGF-1 standard deviation score ≤–3.0, plus normal or elevated GH concentration) or GH gene deletion with neutralizing antibodies to GH. Recombinant IGF-1 products are not intended for use in subjects with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids. Recombinant IGF-1 products have been shown to increase growth velocity in children with short stature who have low IGF-1 serum concentrations and resistance to GH.72,73,74 However, the efficacy of these agents is less than that reported with GH products in patients with GH deficiency.
The recommended dose of mecasermin is 0.04 to 0.12 mg/kg administered by subcutaneous injection twice daily. First year growth and long-term outcomes are best with doses more than 0.1 mg/kg/dose, adjusted for increases in weight as the patient grows. Treatment continues until epiphyseal closure or attainment of full growth potential.72,73 Because of the insulin-like effects of these products, patients should be monitored very closely for hypoglycemia, and the drug should be initiated at the lower end of the dosage range and administered with a meal or snack. Additional adverse effects experienced by patients receiving recombinant IGF-1 products include injection-site reactions, tonsillar/adenoidal hypertrophy, lymphoid hypertrophy, coarsening facial features, anaphylaxis, headache, dizziness, and arthralgia.72,73,74 Intracranial hypertension has been reported in a small number of patients. Additional studies are needed to elucidate the exact role of recombinant IGF-1 products in the management of short stature not caused by GH gene deletion or GH receptor defects.
Ongoing genetic studies are attempting to predict GH response in subjects. There is some evidence to suggest that patients with exon-3 deleted GH receptors or a specific polymorphism in the IGFBP-3 promoter gene have an enhanced response to GH therapy. However, recommendations regarding how therapy can be tailored to maximize patient benefit based on these findings are not available at this time. The large number of GHD disorders vary in phenotype and in biochemical and molecular characteristics thereby likely contributing to the variability of response reported in trials with GH or IGF-1. Given this variability, and in the absence of specific and well-validated indicators of response, therapy must be carefully individualized.75
Evaluation of Therapeutic Outcomes
Appropriate monitoring of therapy for GHD and non-GHD short stature includes regular assessments of height, weight, growth velocity, serum IGF-1 concentrations, and bone age every 6 to 12 months. Additional laboratory tests to monitor for potential adverse effects include serum glucose concentration and thyroid function. The dose of GH will periodically need to be increased as weight increases in growing children.
GH deficiency during childhood results in short stature. Replacement with recombinant GH is considered the mainstay of therapy for patients with GHD short stature, but its use for treatment of non-GHD short stature remains controversial despite FDA approval for this indication. Recombinant GH has proven to be safe for use in children and is associated with few adverse effects. Preparations of IGF-1 may provide benefit for patients with non-GHD short stature. GH regimens can be particularly demanding and inconvenient for pediatric patients because they must be administered by subcutaneous injection. Knowledge of the long-term benefits and risks is critical to the development of rational, cost-effective treatments for patients with short stature.