No large-scale studies evaluating various therapeutic approaches to the treatment of GH excess in pediatric patients are available. Therefore, the optimal treatment of gigantism has traditionally been extrapolated from the adult literature in association with anecdotal case reports detailing the experience of a few clinicians dealing with a handful of patients. As is the case in adults, the three separate modalities available for the treatment of children and adolescents with GH hypersecretion are surgery, radiation and medical therapy. Of these, the greatest recent advances by far have occurred in the realm of pharmacologic agents, resulting in an exciting armamentarium of drugs promising truly enhanced efficacy and excellent safety. Regardless of the individual treatment strategy, the goals of therapy remain the same, namely the restoration of GH and IGF-1 levels to normal ranges (77). Of all parameters investigated, GH levels themselves appear to correlate most with overall morbidity and mortality in acromegaly (78). Table 3 summarizes the current therapeutic options as they pertain to pediatric patients, each of which is discussed below.
Table 3. Clinical Characteristics in Syndromes Associated with Growth Hormones Excess
|
Modality |
Specific Options |
Current Indications |
Pediatric Experience |
|---|---|---|---|
|
Surgery |
Transphenoidal resection |
Pituitary microadenoma or macroadenoma |
Performed safely in children as young as 2 years old |
|
Radiation |
Conventional radiation |
Adjuvant to surgical or medical therapy |
Typically avoided if at all possible, but has been used as adjuvant therapy |
|
Stereotactic radiosurgery, ex: gamma knife |
Adjuvant therapy in patients with residual GH hypersecretion |
No experience with use in children |
|
|
Medical Therapy |
Somatostatin analogues
|
|
Used safely in children with both sporadic and syndromic gigantism for extended periods of time alone and in combination with dopamine analogues |
|
Depot somatostatin analogues
|
Same as above |
Limited experience with use in children but safety and efficacy appear comparable to non-depot preparations |
|
|
Dopamine agonists
|
|
Used safely in children in combination with somatostatin analogues |
|
|
GH receptor antagonists
|
Initial clinical trials suggest excellent efficacy and safety |
Limited experience with use in children |
Transphenoidal resection is the treatment of choice for discreet pituitary microadenomas or macroadenomas (79), with the objective being the preservation of pituitary function in association with cure of the GH excess. Not surprisingly, individual surgeon expertise has a significant impact on the likelihood of success (80), which is exemplified by a rapid normalization of serum GH levels (often within one hour) and response to OGTT. However, while surgery cures the majority of patients with microadenomas, less than 50% of patients with macroadenomas experience this optimal outcome (81). Moreover, extended post-operative follow-up has revealed a gradual return of GH excess over time in a substantial number of patients in whom the disease was previously deemed to be well controlled (82). Experience with surgical treatment of gigantism in children and adolescents has been comparable to that observed in adults (83), and it has been employed safely in patients as young as 24 months (10).
Although traditionally included as a therapeutic option, significant problems exist with the use of conventional radiotherapy in gigantism or acromegaly. These include a low level of efficacy, delayed normalization of GH levels and a high incidence of hypopituitarism. Additional concerns particularly relevant to children include potential neurocognitive effects and the possible development of hypothalamic obesity, both of which have been linked to cranial irradiation in pediatric patients (84). Therefore, radiation therapy would be considered a last resort for the treatment of childhood GH hypersecretion. Improved precision and safety is observed with use of stereotactic radiosurgery in the form of the gamma knife technique, which has been successfully employed as adjuvant therapy in adults with acromegaly (85-87).
Although most commonly considered adjunctive to surgery or radiation, a primary role for medical therapy has always existed for those patients with diffuse pituitary hyperplasia or severe bony deformities precluding a surgical approach. As tremendous improvements in the pharmacologic agents available for use in GH excess continues to evolve, the number of patients offered medical therapy as first-line treatment will surely expand. The three currently existing classes of drugs for suppression of GH and IGF-1 levels are reviewed below.
Ever since their development in the mid-1980’s, long acting analogues of somatostatin have held a pivotal place in the medical treatment of GH excess. These agents exert their effect through selective binding to somatostatin receptors within somatotroph adenomas (88). By far the greatest experience in the United States has been with octreotide, which is typically administered subcutaneously in three divided doses. Short-term administration of octreotide results in a decrease in GH levels within one hour in > 90% of patients with acromegaly (89), while sustained use normalizes GH and IGF-1 levels in up to 65% of patients (90). Experience with the use of octreotide in children has been similarly favorable, where it has been beneficial in the treatment of sporadic as well as syndromic gigantism (9;(91;92). Continuous subcutaneous infusion of octreotide has also resulted in superior efficacy in controlling GH hypersecretion in a pubertal patient (93). Long-acting depot preparations of octreotide in the form of Sandostatin LAR and SR-lanreotide are also available, in which a slow release of drug is achieved through degradation of a polymer in which microspheres are encapsulated (94) . This allows for monthly IM administration, resulting in a safety and efficacy profile that is comparable to or improved in contrast to traditional dosing (95). These slow-release preparations have also been found to have utility in the treatment of ectopic forms of GH excess (96), and in the treatment of MAS associated gigantism (97). The development of novel somatostatin analogues have the potential to improve efficacy over existing compounds (98). The major side effect of all the somatostatin analogues is a significantly increased risk of biliary sludge and gallstones after sustained use, necessitating periodic ultrasound examinations in patients treated long-term (99).
Although rarely effective alone, dopamine agonists have a valuable role as adjunctive agents in the treatment of GH excess. Due to their suppressive effects on prolactin, these drugs are particularly advantageous when hyperprolactinemia is present, as is often the case in childhood-onset gigantism. Both bromocriptine and the more potent dopamine agonists such as cabergoline have been administered to children in combination with octreotide long-term with no apparent adverse effects (35;39).
The latest development in the realm of medical therapy has been the emergence of pegvisomant, a genetically engineered human GH analogue that acts as a highly selective GH antagonist (100). This is achieved through alterations in affinity binding of pegvisomant compared to the native GH molecule (101), resulting in prevention of the normal extracellular dimerization of the growth hormone receptor. Administration of pegvisomant long-term to adults with acromegaly has been shown to result in normalization of serum IGF-1 levels in 97% of patients (102). Despite these extremely promising results, the implications of the nearly ubiquitous elevations in serum GH levels observed in conjunction with pegvisomant treatment have not been completely investigated. Rare reports of an increase in tumor volume and of the development of abnormal liver enzymes have also been described in patients receiving pegvisomant (103). Thus far, only limited experience with the use of pegvisomant for the treatment of gigantism in children is available (104).
Depending on the absolute height and the degree of growth potential remaining, one of the goals in the treatment of gigantism may be prevention of further linear growth. When this is the case, acceleration of epiphyseal fusion can be achieved with exogenous sex steroids (105). Short-term administration of both high dose testosterone and estrogen have been utilized for this purpose in children with gigantism, resulting in significant improvements in terms of adult height (106;107).