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Therapy for idiopathic GHD: take a break?
Some research has physicians questioning the concept of a trial off of GH therapy during childhood.
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Since its approval in 1985, recombinant human growth hormone has been used to treat children with growth hormone deficiencies in an effort to improve their linear growth. Although the beneficial effects that growth hormone has on these children are widely accepted, attempts to determine the best treatment method for handling the transition period from adolescence to adulthood have sparked some controversy in the endocrinology community.
“The majority of kids in this country being treated with GH are, from what we can tell, healthy children who have nothing wrong with them aside from being below the growth curve. They happen to test low on a provocative GH stimulation test but have no explanation for it — their MRI scan is normal," David B. Allen, MD, professor of pediatrics and director of endocrinology and endocrine fellowship training at the University of Wisconsin Children’s Hospital at Madison, told Endocrine Today.
A paper published in the Journal of Clinical Endocrinology and Metabolism in 1997 supports Allen’s point. Maithe Tauber, MD, PhD, and colleagues from France assessed GH status in 131 young adults treated between 1980 and 1994 for partial or complete GHD. Patients had both idiopathic (n=121) and organic (n=10) GHD and were taken off of GH therapy between 1992 and 1994.
Of the 33 patients with complete GHD, 36% had normal GH peaks. Of the 98 patients with partial GHD, 71% had normal GH peaks. Overall, 62% of patients had a normal GH peak above 10 mcg/L. Based on these findings, the researchers concluded that GHD patients should undergo reevaluation after completing GH therapy.
Conflicting data
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Photo by Chris Frazee |
Deciding when adolescents should be considered for adult GH therapy, who should be transitioned and how the decision should be made are difficult questions due to conflicting research published in peer-reviewed literature.
Currently, standard practice is to strongly consider and eventually treat adolescents with multiple pituitary hormone deficiencies or low IGF-1 combined with an organic or congenital anomaly, history of irradiation to the hypothalamic-pituitary region or a genetic/molecular defect, according to the Endocrine Society’s clinical practice guideline on the evaluation and treatment of GHD.
Although experts will agree that these adolescents with prior documented genetic or acquired pituitary lesions should be transitioned, the patients with isolated idiopathic GHD are the ones whose treatment remains debatable.
“The controversial issue here is whether or not these kids, who are likely to eventually show normal GH secretion, should continue to be treated without interruption until they have completed their linear growth,” Allen said.
In a study published in the Journal of Clinical Endocrinology and Metabolism in 2006, Stefano Zucchini, MD, and colleagues from the Malpighi Hospital in Bologna, Italy, conducted a prospective, non-randomized, open-label study to compare the statural outcome of patients with isolated GHD who normalized GH secretion at puberty with those who had persistent GH deficiency. Patients were treated with GH after retesting. Sixty-nine patients diagnosed with isolated GHD before puberty were retested after two years of therapy and after the onset of puberty. Therapy was discontinued if GH peak at retesting was >10 mcg/L, which occurred in 44 patients (63.7%).
The researchers reported no differences between participants with confirmed GHD and the others in terms of height deficit at diagnosis, first-year growth response to GH, age and height at the onset of puberty, or height and IGF-1 level at retesting.
Mean adult height was 165.1 cm in boys treated until adult height vs. 164 cm in boys who discontinued therapy at retesting, according to the study. In girls, those treated until adult height had a mean adult height of 153.2 cm vs. 152.9 cm in those who discontinued therapy at retesting.
“This is a provocative idea. If it works, there is conceivably a reasonable financial savings that could be achieved and less hassle for the patient,” Mitchell Geffner, MD, professor of pediatrics at the Children’s Hospital Los Angeles, told Endocrine Today. “However, it assumes that by stopping therapy, patients would test out normal at that point just as often as they would later.”
Based on their findings, the researchers concluded that “it seems convenient, in subjects with non-severe GHD, to retest GH secretion at mid-puberty and to withdraw treatment for the subjects that are no longer deficient.”
The traditional approach
 Mitchell Geffner |
Some experts argue for treating children with isolated GHD until they have completed epiphyseal fusion and have reached adult height, a widely practiced approach. A paper by Sally Radovick, MD, division director of pediatric endocrinology at Johns Hopkins Children’s Center in Baltimore, outlined the who, what, why and when of transitioning from pediatric to adult GH therapy based on her own practices and data published in the literature.
According to Radovick, whose paper was published in the Journal of Clinical Endocrinology and Metabolism, the criteria for defining the achievement of near final adult height and completion of skeletal growth vary. Although most studies use a growth velocity of <2.5 cm/year for attainment of final height, many retrospective studies use a growth velocity <1 cm/year.
“In practice, if a child has achieved 98% to 99% of final adult height (bone age of 14 to 15 in girls or 16 to 17 in boys) and has a growth velocity <3 cm/year on adequate GH replacement, we consider reevaluation for transitional therapy,” she wrote.
According to the Growth Hormone Research Society’s consensus statement on the diagnosis and treatment of GH deficiency, “the need for continuation of GH replacement should be evaluated following completion of statural growth (usually before the age of 20 years).”
 Peter Clayton |
“The traditional consensus view is that if you have committed to treating a child for GHD, you treat them through childhood and through puberty and when they stop growing, you retest them,” said Peter Clayton, MD, professor of child health and pediatric endocrinology at the University of Manchester in the United Kingdom.
According to Clayton, the alternative view has come about as a result of studies such as Tauber’s; experts are questioning the validity of the original diagnosis of GHD and whether therapy can be discontinued earlier in childhood when a positive outcome has been achieved.
“There are a couple of papers in the literature related to stopping children early and retesting them, but it has never been put through a controlled trial. The types of kids we target for transitional GH replacement are those who have organic problems, and you would never dream of stopping them at the onset of puberty,” he told Endocrine Today.
GH holiday
A number of studies assessing the safety and efficacy of taking a GH “holiday” during the transition period have recently been published, including a paper by Nelly Mauras, MD, chief in the division of endocrinology at Nemours Children’s Clinic in Jacksonville, Fla., Geffner and colleagues.
They conducted a two-year multicenter study that included 58 patients with GHD; mean age of the patients was 15.8 years. Patients were near completion of linear growth and still being given GH during baseline measurements. After four weeks of GH discontinuation, patients were retested. Those with GHD were randomly assigned to GH (n=25; ~20 mcg/kg per day) or placebo (n=15).
At baseline and after two years, both groups had normal lipid and carbohydrate metabolism levels, body composition, bone mineral density, cardiac function, muscle strength and quality of life. Though the researchers observed a decrease in IGF-1 levels for all patients, those in the GH group had lower IGF-1 levels (P=.013). At 12 months, patients in the GH group had a greater increase in lean body mass, but the increase was not superior at 24 months.
Some research, however, has challenged these findings by demonstrating risks to body composition, BMD, quality of life and cardiac function associated with taking a break from GH therapy.
Stephen M. Shalet, MD, professor of endocrinology at Christie Hospital in Manchester, United Kingdom, and colleagues explored the efficacy of continuing GH therapy after attaining final height in patients with childhood-onset GHD who had discontinued therapy at final height.
The randomized, multinational, open-label study included 149 patients with childhood-onset GHD who had been treated for at least one year and had been off of therapy for a minimum of six weeks to a maximum of five years. Patients had a height velocity <1 cm per year. Shalet and colleagues randomly assigned patients to one of three groups: 25 mcg/kg per day (n=59; 0.18 mg/kg per week; pediatric dose), 12.5 mcg/kg per day (n=58; 0.09 mg/kg per week; adult dose) and control (n=32).
After two years, they reported changes in bone-specific alkaline phosphatase (P=.004) and type I collagen C-terminal telopeptide–creatinine ratio (P<.001) in both GH groups, compared with controls. Total bone mineral content increased in the adult (9.5%), pediatric (8.1%) and control (5.6%) groups, according to results of the study published in the Journal of Clinical Endocrinology and Metabolism in 2003. The most predominant increase at the lumbar spine compared with the femoral neck or hip (11%; P=.015).
“The truth is most patients with bona fide GHD do not want to stay on, no matter how well we prepare them,” Geffner said. “From the first day they get a GH shot and they find out that they might be on it for the rest of their lives, when they are finished growing most of them want a trial off.”
“If a patient is deficient, it seems illogical to reach a certain point in life and say, ‘I’m going to stop with GH therapy,’ particularly when it is at a point in life when there is good evidence that treatment is still needed,” added Clayton. “It would not make sense for a patient with hypothyroidism to reach a point in life and say, ‘I do not need thyroxine anymore.’ So, my default position is to always consider replacement as long as there are good indications such as retesting low.”
More data needed
Some experts agree that more data are needed to address some of these crucial issues.
“We do not have all of the answers; there is at least one conflicting report, if not others. So, if not everyone is convinced and there are not enough data, it is the same old story and more research needs to be conducted,” Geffner said.
Until more data are available, the approach of treating an adolescent during the transition period should be individualized.
“People will quibble about whether these patients should be taken off at all. Clearly there is no definite right or wrong answer that is applicable to patients in general — this therapy decision should be highly individualized,” Allen said.
According to the Growth Hormone Research Society’s consensus document, “GH status should be reevaluated in the transition age for continued GH replacement to achieve full somatic development. Replacement therapy should be individualized based on the titration against the serum IGF-I levels and the absence of adverse events.”
 Ron Rosenfeld |
“There should be a bit of a default position in anything except the most severely affected children,” Allen said. “The default position should be to prove that there is a deficiency that is progressing into adulthood. It is a decision and a recommendation that will affect the patient for years upon years, so whether an adolescent needs adult GH therapy is an important decision to make,” he said.
Patient follow-up is also an important concern among most endocrinologists, especially among those with patients who decide to discontinue therapy for a period of time.
“True GHD does not go away; typically, it is a lifetime disease. The child who has been diagnosed and treated as GHD deserves a fresh reevaluation during the transition phase,” Ron Rosenfeld, MD, senior vice president for medical affairs at the Lucille Packard Foundation for Children’s Health, told Endocrine Today.
Reevaluating the patient provides the physician with adequate data to help decide whether or not to treat the patient, as opposed to making the decision based on an impulse, according to Rosenfeld.
“These patients, under any circumstance, even if they opt not to take GH, should not be lost to follow up; they need lifelong medical care at a minimum. Even for those that are obstinate and do not want to consider taking GH, someone who knows what to look for needs to at least keep tabs on them,” Geffner said. – Stacey L. Adams
Can an adolescent with bona fide GHD have a trial off of therapy?
For more information:
- Ho KKY. 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. Eur J Endocrinol. 2007;157:695-700.
- Mauras N, Pescovitz Hirsch O, Allada V, et al. Limited efficacy of growth hormone (GH) during transition of GH-deficient patients from adolescence to adulthood: a phase III multicenter, double-blind, randomized two-year trial. J Clin Endocrinol Metab. 2005;90:3946-3955.
- Molitch ME, Clemmons DR, Malozowski S, et al. Clinical practice guideline: Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2006;91:1621-1634.
- Radovick S, Divall S. Approach to the patient: Approach to the growth hormone-deficient child during transition to adulthood. J Clin Endocrinol Metab. 2007;92:1195-1200.
- Shalet S, Shavrikova E, Cromer M, et al. Effect of growth hormone (GH) treatment on bone in postpubertal GH-deficient patients: A 2-year randomized, controlled, dose-ranging study. J Clin Endocrinol Metab. 2003:88:4124-4129.
- Tauber M, Moulin P, Pienkowski C, et al. Growth hormone (GH) retesting and auxological data in 131 GH-deficient patients after completion of treatment. J Clin Endocrinol Metab. 1997;82:352-356.
- Zucchini S, Pirazzoli P, Baronio F, et al. Effect on adult height of pubertal growth hormone retesting and withdrawal of therapy in patients with previously diagnosed growth hormone deficiency. J Clin Endocrinol Metab. 2006;91:4271-4276.