by Madhusmita Misra, M.D.
NEPTCC Newsletter MGH Neuroendocrine Center Bulletin Vol 11, Issue 2, Fall/Winter 2005
The aim of growth hormone (GH) treatment in childhood has primarily been to optimize growth potential and adult stature in children testing as GH deficient based on GH stimulation tests. Therapy was traditionally stopped when growth velocity decreased to less than 1 cm per year, or at a bone age of 15 years in girls or 17 years in boys, when less than 1% of growth potential remained. In the past few years, studies have demonstrated the need for GH replacement in adults with GH deficiency, and have reported improvements in body composition (decreased fat mass and increased muscle mass), increases in bone density, reduction of cardiovascular risk and improvement in quality of life following GH replacement. This raises the issue of lifelong GH therapy and for many children who believed their daily injections would end once adult height was achieved, causes significant disappointment. One question is whether GH treatment may be discontinued for some time in this situation and then restarted without jeopardizing potential beneficial effects of GH replacement. In addition, given that criteria for GH therapy are relatively broad in childhood, it is important to identifytruly GHdeficient individuals rather than continue GH replacement in all young adults, some of whom may no longer test as GH deficient. This is particularly important because GH therapy is not without certain side effects; amongst these the risk of developing impaired glucose tolerance and less commonly, frank diabetes. The other important aspect is the tremendous cost of GH replacement.
Important considerations at the end of statural growth thus include:
- Is the individual truly GH deficient based on repeat testing?
- What is the appropriate dose of recombinant human GH during the transition from childhood to adult replacement?
- Is a period off GH replacement (GH ‘holiday’) possible and are there subsequent effects on body composition, bone density, cardiovascular risk and quality of life?
Is the Individual Truly GH Deficient?
GH secretion varies with age, and criteria for the diagnosis of GH deficiency differ in children compared with adults. Children secrete more GH than adults, in particular during the pubertal years, with GH levels peaking around mid to late puberty (earlier in girls than in boys), following which GH secretion gradually declines. In children, a peak GH response on two provocative tests of less than 5 ng/ml suggests complete or severe GH deficiency, whereas a peak GH response between 5-10 ng/ml is termed partialGH deficiency. This is in contrast to adults, in whom a peak GH response of less than 3 ng/ml with the insulin tolerance test, or less than 4-9 ng/ml on the GHRH-arginine test constitutes severe GH deficiency. The cut-off for diagnosis of GH deficiency in latepuberty and in young adults is, however,unclear. Given that GH has importanteffects on bone andbody composition at this time of life despite growth beingalmost complete, and because GH levels,although declining, are still higher than inadults, it is suggested that a cut-off of 5ng/ml rather than 3ng/ml be used todefine severe GH deficiency in thistransition period.
Re-testing an individual previouslydiagnosed with GH deficiency is particularlyimportant given the diagnostic inaccuraciesassociated with GH stimulation testing.In addition to the obvious false positivesassociatedwith the cut-offs used inchildhood, fallacies may occur dependingon the specificstimulation test selected,and the different GH assays in use. Theinsulin tolerance test, which is thegoldstandard for diagnosis of GH deficiency, israrely used in children because of the risksfromhypoglycemia, and the GHRH-argininetest, which is as accurate as theinsulin tolerance test inadults withouthypothalamic dysfunction, has not provensimilarly useful in children. This has resultedinthe use of a variety of provocativetests depending on the age of the child,side effects, and thepreferences of the pediatric endocrinologist. In addition todiagnostic errors associated with theprovocative stimulus used, there are errorsobserved related to lack of sex steroid primingprior totesting in children who are prepubertalor in very early puberty, particularlin situations of constitutional delay in growth and development.
In general, teenagers most likely to continue to test severely GH deficient are those with:
- (i) Multiple pituitary hormone deficiencies
- (ii) Peak GH response of less than 5 ng/ml on initial testing
- (iii) Structural hypothalamic-pituitaryand central nervous system abnormalities(iv)Historyof hypothalamic-pituitaryirradiation.
Conversely, a normal peak GH responseonrepeat testing is more likely in individualswith:
- (i) Isolated idiopathic GH deficiency(30-70%subsequently have a normalresponse)
- (ii) Partial GH deficiency (~77% arenormal on retesting) SeeFigure 1.
Overall, the peak GH response is normalin 20-87% of young adults who werediagnosed with and treated for GH deficiencyin childhood. Some endocrinologistsstop treatment inchildren with partialGH deficiency when the 10th percentilefor height is achieved, or puberty begins;documentation of subsequent normalgrowth velocity in these children obviates retesting.
"The recognition of a GH
deficiency syndrome in
adults necessitates identification
of adolescents and
young adults who may
warrant continuation of
treatment after statural
growth is complete."
Currently,discontinuation of treatmentand reassessment of GH secretory status isnecessary before adult replacement can beinitiated. Discontinuation of GH treatmentfor a period ofthree months is sufficient; reports exist of recovery of the GH axiseven four weeks after interruption of GH therapy. It is interesting to note that at least one study has demonstrated normalized GH responses to stimulation testing in 29% of children even during daily GH replacement.
The European Society of PediatricEndocrinology has recently proposed newguidelines based on serum IGF-I levels and GHstimulation testing (insulin tolerancetest, arginine or glucagon). Continuationof GH therapy without interruption is suggested for teenagers with severe congenital or acquired hypopituitarism and multiple hormonal deficiencies. In adolescents with high likelihood of severe GH deficiency, measuring IGF-I after a month of discontinuing GH, and restarting GH treatment if serum IGF-I is less than -2 S.D.s is recommended. For adolescents with IGF-I levels greater than -2 S.D.s, a GH stimulation test is suggested, withGH treatment to be restarted inpatients with a low peak GH response. Foradolescents with low likelihood of severeGH deficiency, both serum IGF-I and GH stimulation testing are recommended, with GH therapy to be restarted if IGF-I and peak GH response are low, to be stopped if both are normal, and further follow up suggestedif results are discordant.
What is the Ideal Dose of rhGH DuringtheTransition from Adolescent to Adult GHReplacement?
This is an important question, which hasnot yet been fully addressed. Based onhigher GH concentrations in children andadolescentscompared with adults, the replacement dose in children is higher (30-40 mcg/kg/day or 0.22-0.30 mg/kg/week)compared with adults (2-12 mcg/kg/day). The optimal dose during the transitionfrom adolescent to adult replacement is likely somewhere in between, given that GH concentrations gradually decrease after puberty to adult levels. At least one study has suggested that a higher dose (25 mcg/kg/day) may have greater beneficial effects compared with a smaller dose (12.5 mcg/kg/day), although not all studies demonstrate a dose effect. Dose titration based on IGF-I levels for age is an alternative method of determining the optimum GH dose. This is even more important given the recently demonstrated differences in IGF-I levels depending on gender, with lower levels of IGF-I in women than in men.
Is a Drug ‘Holiday’ Possible and How Long Should This Last?
Benefits of a drug holiday include temporary freedom from daily injections, and for the young adult to feel that plans made in childhood are being honored. Their sense of autonomy is maintained, and this period off GH allows for re-testing to be performed. For individuals that are not GH deficient on re-testing, there is no indication for restarting therapy. However, in individuals continuing to be severely GH deficient, the question arises as to when replacement should be resumed.
In addition to results of stimulation testing, this may be influenced by whether symptoms of GH deficiency develop in the young adult. Early development of clinical features makes the decision to re-start therapy relatively simple. Features of adult GH deficiency include an increase in fat mass, a decrease in muscle mass resulting in decreased strength and exercise capacity, as well as a deterioration of quality of life.
However, an insidious development of symptoms may cause the individual to miss early features of adult GH deficiency, and this may be exaggerated by a subconscious reluctance to return to daily injections. In addition, some of the deleterious effects of GHD in adults, such as osteoporosis and increased cardiovascular risk are silent until fractures or cardiovascular events occur. Another major issue is that patients this age are often lost to follow up. They may no longer feel comfortable in a pediatrician’s office, yet not have an established relationship with an adult care provider familiar with the use of GH. Individuals with multiple pituitary hormone deficits, those with evidence of severe GH deficiency, associated structural central nervous system abnormalities, and past history of irradiation are more likely than others to manifest the adult GH deficiency syndrome and be seen by an adult endocrinologist
Of importance is the effect of GH on bone and body composition in the young adult. Healthy adolescents 17-21 years old exhibit increased lean body mass and handgrip strength over a two-year period but this does not occur in untreated GH deficient adolescents. Small studies in adolescents treated with GH during adulthood have demonstrated that fat mass increases by about 5% and muscle mass decreases commensurately within a year following discontinuation of GH, and reductions occur in muscle strength, muscle size and fiber area. Increases in trunk fat have been reported in GH deficient adolescents following discontinuation of GH therapy (Figure 2)
therapy for a period of
one to three months is
advisable prior to
Adolescence and young adulthood are the periods of life when bone mass accrual is maximal, culminating in achievement of peak bone mass. This raises concern that cessation of GH replacement may result in permanent deficits, particularly of bone mass, resulting in increased fracture risk in later life. A recent study of 40 GH deficient adolescents found no beneficial effects of GHreplacement at a dose of 20mcg/kg/day, (i.e. about half the pediatric GH replacement dose), versus placebo on bone density, body composition, cardiac function, muscle strength, carbohydrate or lipid metabolism, or quality of life over a two year period. A trend towards lower bone density at the lumbar spine was, however, noted in the group receiving placebo. A significant difference may have been evident with a larger study, with a higher retention rate (only two thirds of the subjects completed the study) or with higher doses. Although continued increase in bone mass has been demonstrated up to two years after discontinuation of GH therapy, investigators have reported that attainment of peak bone mass is slower and ultimate peak bone mass lower than in controls, with rapid decline in bone density occurring two years after attainment of peak bone mass.
Beneficial effects on metabolic profiles and specific quality of life measures have been reported in other studies in GH deficient adolescents continued on GH after completion of growth (Figure 3). Larger studies are awaited to provide definitive information regarding the safety and duration of a drug holiday in older teenagers and young adults.
The recognition of a GH deficiency syndrome in adults necessitates identification of adolescents and young adults who may warrant continuation of treatment after statural growth is complete. Discontinuation of therapy for a period of one to three months is advisable prior to re-testing. A peak GH response of less than 5 ng/ml suggests the need for adult GH replacement therapy in transitional doses to begin with, to be gradually weaned to adult doses over time. Rapid resumption of GH replacement is especially recommended in individuals with clinical evidence of adult GH deficiency. However, complete reliance on symptoms alone may delay restarting therapy because there are no early symptoms of some features of GHD, or the onset of symptoms may be insidious, and because of the risk of loss to follow up. A drug holiday is possible, but the duration of this period off GH should be balanced against risks of impaired bone mass accrual, increases in fat mass and decreases in muscle mass leading to poor muscle strength, increased cardiovascular risk and impaired lipid profiles, and a deterioration in quality of life. Current data suggest that the duration of discontinuation of GH therapy should not last longer than two years pending further data. Interaction between the pediatric and adult endocrinologists during the transition period is crucial to determine an optimal management plan for each young adult.
- Allen DB. Pediatrics. 1999; 104(4 Pt 2): 1004-10.
- Attanasio AF, et al. J Clin Endocrinol Metab. 2005; 90:4525-9.
- Clayton PE, et al. Eur J Endocrinal. 2005; 152: 165:165-70.
- Mauras N, et al. J Clin Endocrinol Metab. 2005; 90:3946-50
- Saggese G, et al. J Endocrinol Invest. 2004; 7:596-602.
- Shalet S. Horm Res 2004; 62 (suppl 4):15-22.
~ MASSACHUSETTS GENERAL HOSPITAL
Acromegaly Patient Education Day ~
On April 25, 2005, the Massachusetts General Hospital Neuroendocrine Clinical Center hosted patients and their guests for an informative Acromegaly Patient Education Day.
Attendees from 15 states learned about many aspects of the disorder from endocrinologists, nurses and an expert pituitary surgeon.
Slide presentations and a video of an actual transsphenoidal pituitary operation were highlighted by question and answer periods.
Patients with acromegaly shared their stories, providing a unique opportunity for patients with this rare disorder to meet other people with the same condition.
~ RESEARCH STUDIES AVAILABLE ~
Patients may qualify for research studies in the Neuroendocrine Clinical Center. We are currently accepting the following categories of patients for screening to determine study eligibility. Depending on the study, subjects may receive free testing, medication and/or stipends.
~ Physicians' Pituitary Information Service ~
with questions about pituitary disorders may contact:
Dr. Biller or Dr. Klibanski at
(617) 726-3965 within the Boston area or toll free at (888)
or e-mail to email@example.com
~ MGH Neuroendocrine Clinical Center
Services Available ~
Facilities The Neuroendocrine Center is located on the 1st floor (Suite 112) of Zero Emerson Place at the Massachusetts General Hospital. A test center is available for complete outpatient diagnostic testing, including ACTH (Cortrosyn) stimulation; Insulin tolerance; CRH stimulation; Oral glucose tolerance and growth hormone reserve testing. Testing for Cushing's syndrome can also be arranged, including bilateral inferior petrosal sinus ACTH sampling for patients with ACTH-dependent Cushing's syndrome.
Speakers The Neuroendocrine Center offers speakers on a wide variety of topics. Lectures, rounds, and small symposia can be arranged.
Neuroendocrine Clinical Conference A weekly interdisciplinary conference is held to discuss all
new patients referred to the Neuroendocrine Center and to review patient management issues. It is a multidisciplinary conference, attended by members of the Neuroendocrine, Neurology, Neurosurgery, Psychiatry and Radiation Medicine services. Physicians are welcome to attend and present cases.
Neuroendocrine Lecture Series A bimonthly conference is held on didactic and research topics
related to Neuroendocrinology. Attendance is open to all interested medical personnel.
Physicians’ Pituitary Information Service Physicians with questions may contact Dr. Biller or
Dr. Klibanski at (617) 726-3965 within the Boston area or toll free at (888) 429-6863, or e-mail to
Scheduling Outpatient clinical consultations for patients with pituitary disorders can be arranged by calling the Neuroendocrine Center Office at (617) 726-7948.