Pituitary Disorders
Alteration of Timing of Skeletal Maturation by Controlling Timing of Puberty
GH treatment often falls short of helping patients achieve their full genetic height potential (within mid-parental height range). Patients with multiple pituitary hormone deficiencies (MPHD) generally have a slightly better long-term height outcome compared with patients with isolated GHD, related to lack of endogenous puberty.64
Those
patients with isolated GHD enter puberty at a typical or slightly delayed age. In contrast, patients with MPHD are often placed on therapy to induce puberty at an older age, after the clinician has observed for their spontaneous entry into puberty.59,65
Treating with GH in combination with therapy to induce pubertal delay can prolong the total period of time that the adolescent can continue to keep growing taller.2,3,66
In brain tumour survivors with
GHD treated with GH, use of gonadotrophin-releasing hormone analogue (GnRHa) therapy improved adult height compared with patients not treated with GnRHa.3,66–68
Overall, adult height in cancer
When height prediction is adversely affected by early puberty, the combination of GnRHa and GH improves prospects of achieving target height.3,66–68
GH therapy may also increase adult height potential.69–71
Using aromatase inhibitors in adolescent boys on Combination
of GnRHa and aromatase inhibitor may have even more benefit in preserving growth potential.72
Utilisation of Pubertal Doses of Growth Hormone Compared with standard GH doses, high-dose GH therapy in adolescents (pubertal dosing) increased near-adult height and height SD without significantly increasing skeletal maturation and without important side effects.57,73
However, preliminary analysis suggests that GH dose may have only a small effect on total pubertal growth.74
Development of Depot Dosing of Growth Hormone The need for daily injections is a potential barrier contributing to inconsistent use of GH. Maintaining IGF-1 levels in a therapeutic range should be possible without daily injections.75,76
One option is to
use a sustained-release form of GH that might be given once each week.75,77,78
A prior depot GH product could be given once weekly or every two weeks, but efficacy was not as good as daily GH, so it is no longer available for use in the US.79
There is a theoretical concern that depot GH doses are non-physiological. With administration of a depot GH product, serum GH levels will be above physiological levels for a higher percentage of time each day. The typical physiological pattern (described above) includes a GH peak, then a return to unmeasureable baseline, then another peak, etc (two to six pulses each night). In contrast, depot GH yields levels that are more like those seen in acromegalic patterns, which never decline to baseline (see Figure 4). It is not currently known whether there is a higher risk of cancer with sustained GH elevation.
Matching of Physiological Levels and Pattern of Growth Hormone Secretion
In most instances of GHD in children, hypothalamic deficiency of GHRH is the cause (with intact pituitary GH secretory capability). Therapeutic use of GHRH to enhance GH secretion is limited by the short duration of action of GHRH.17,75,80
GHRH therapy produces pulsatile release of GH, similar to normal physiology; however, 44
Improvement of the Process of Transition from Paediatric to Adult Care
For optimal GH therapy, it is important to perform re-evaluation of GH release at the time of achieving adult height, in order to see whether there is a continued need for GH therapy as an adult (adult GHD).84–86
In
childhood-onset adult GHD, stopping GH therapy at reaching adult height can lead to decreased QoL, abnormal lipid panel, truncal adiposity, decreased muscle, fatigue, atherogenic risk, cerebrovascular and cardiac morbidity/mortality and decreased bone mineral density. Those with severe GHD will benefit from pausing GH therapy only long enough for re-evaluation.84
In patients in whom it is clear that there will
be persistence of GHD in adulthood, as in an organic aetiology or MPHD, continuing GH therapy during transition to adult care may be helpful to in order to optimise bone mineral and body composition and to avoid patients being lost to follow-up.59,85,86
Perspectives for the Future
Options for optimising GH therapy in childhood GHD include: •
prevention of GH deficiency when possible; •
• •
• • • •
early identification and initiation of GH treatment when a child is young;
adherence to the prescribed therapy;
adjustment of GH dose on an individual basis to achieve close to ‘target’ results;
regulation of timing of puberty;
consideration of higher GH doses, given daily; development of a depot GH preparation;
development of GHRH/peptide therapy in order to match the EUROPEAN ENDOCRINOLOGY
survivors with GHD treated with GH has improved during the last 25 years.3
therapy using GHRH requires several injections daily or an infusion. If it were possible to develop a depot form of GHRH, then it could be given monthly, every three months, yearly and theoretically still could induce pulsatile GH release.75
A depot GH releaser should be effective
at producing a pulsatile GH pattern unless there has been a direct pituitary insult.81
induce physiological pulses are not currently practical.
Slow-release preparations of GHRH might improve adherence if found to have long-term efficacy and safety.50
Studies of a new long-acting
GHRH analogue have shown increases in trough GH levels and enhanced GH pulsatility.75
analogue, mean plasma GH increased by two- to 10-fold for six days or more with preserved pulsatility and mean plasma IGF-1 increased by 1.5- to three-fold for nine days or more. The depot GHRH was well tolerated in healthy adults, with no significant side effects.17,80
After a single injection of long-acting GHRH Intravenous or subcutaneous GH infusion pumps to
A depot
therapy that releases pulses of GH could mimic normal physiology better than weekly or even daily GH injections.
Development of an Alternative Delivery System Options for alternative delivery of GH are limited because of the size of the GH molecule. Inhaled GH was tested and found to have only 3.5% bioavailability, but was tolerated well. IGF-1 failed to rise in 25% of the GHD children treated.82
Transdermal administration is not
possible with GH, because the protein is too big. In addition, GH itself is not active orally, as it is digested. A better option would be to work on further development of an oral GH-releasing peptide (GHRP) that could cause pulses similar to GHRH or ghrelin. Orally active secretagogues (ghrelin analogues) release GH, but have not yet been tested for prolonged therapy in children.83
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