Since 1996, recombinant human growth hormone has been an FDA-approved therapy for adults with growth hormone deficiency.
In this patient population, GH replacement has generally been considered safe and effective when used and monitored appropriately. The Endocrine Society Clinical Practice Guideline on Evaluation and Treatment of Adult Growth Hormone Deficiency, updated in 2011, has provided new clarity regarding the diagnosis of GH deficiency, as well as the management of adults on GH replacement.
These guidelines identified adults at risk for GH deficiency (GHD), including those with sellar or parasellar lesions, head injury, surgery or radiation therapy, subarachnoid hemorrhage, as well as those with childhood-onset GH deficiency (COGHD). Idiopathic GHD of adult onset was considered to be very rare. Two GH stimulation tests were suggested to make the diagnosis of GHD in this population to avoid patient misclassification as a result of false-positive results of any single stimulation test.
Nicholas A. Tritos
Retesting of COGHD patients after completion of statural growth was recommended, recognizing that a substantial fraction of these patients may recover normal GH secretion in adulthood. It was also recommended that COGHD patients at high risk for persistent GHD in adulthood, including those with structural sellar lesions and multiple pituitary hormone deficiencies or those with established genetic causes of hypopituitarism, may forgo GH stimulation testing in adulthood. In these patients, establishing low serum insulin-like growth factor I levels, obtained 1 month after GH discontinuation, was recommended as being sufficient to establish the presence of persistent GHD in adulthood.
Both the insulin tolerance test (ITT) and the growth hormone-releasing hormone (GHRH)–arginine stimulation test were recommended as being sufficiently accurate to diagnose GHD in adults. Some limitations of the GHRH–arginine stimulation test were reviewed, including the possibility of obtaining falsely normal test results in patients who have received cranial radiation therapy within the previous 10 years, and the possible use of BMI–dependent GH diagnostic cut-points for adult GHD. The glucagon stimulation test was suggested as a useful alternative to ITT and the GHRH–arginine stimulation test. This is particularly noteworthy, as GHRH is currently not available in the United States. In addition, ITT is contraindicated in a subset of adults at risk for GHD (including older patients, those with cardiovascular disease or seizures).
The documented benefits of GH replacement in adults were carefully reviewed in the 2011 Endocrine Society Guidelines, including: improvements in quality of life; body composition; bone mass and CV function; increase in exercise capacity and favorable effects on serum lipids; systemic inflammatory markers; and intima-media carotid thickness. It was noted, however, that GH replacement has not been shown to improve the increased mortality associated with hypopituitarism in clinical trials.
Other study results
A recent open-label, observational study of adult GH replacement (for 33 months), published by Jorgensen and colleagues revealed similar benefits of GH therapy on body composition, bone mass, serum lipids and quality of life. In another observational study by Spielhagen and colleagues, involving analysis of data on long-term (4-10 years) GH replacement from the German subpopulation of the KIMS database, there was a sustained improvement in quality of life over the treatment period, but no long-term significant change in lipids or glucose levels. In a large observational study by van Bunderen and colleagues, the mortality of Dutch GHD adults on GH replacement was studied in comparison to the general population. Mortality was increased in women, but not in men receiving GH replacement. In addition, CV mortality was increased in women, but mortality secondary to malignancies was not elevated in patients of either gender. A control group of unreplaced GHD adults would be needed to fully characterize the effects of GH replacement on mortality.
In the 2011 Endocrine Society Guidelines, it was also recognized that GH replacement in older adolescents and young COGHD adults is associated with benefits with regards to bone and muscle mass after the attainment of adult height. It was, therefore, recommended that COGHD patients with persistent GHD on retesting (performed after completion of statural growth) be offered GH replacement to optimize skeletal muscle and bone mass during the transition years.
Another issue that was reviewed in the Guidelines involves the consequences of GHD in adults with treated acromegaly and the possible effects of GH replacement. It was recognized that some studies have suggested that quality of life is decreased in GHD adults with treated acromegaly. It was also recognized that the effects of GH replacement have not been clearly established in this population, as available studies showed mixed results.
The interaction between GH replacement and either adrenal or thyroid function was highlighted in the Guidelines. Several lines of evidence have suggested that deficiencies in adrenal or thyroid function may be unmasked by GH replacement. In addition, in patients with established central hypoadrenalism or hypothyroidism, replacement doses may need to be increased after beginning GH replacement. It was, therefore, suggested that monitoring of thyroid and adrenal function is advisable in hypopituitary patients commencing GH replacement.
The safety of GH replacement was carefully reviewed, as well. Side effects of GH replacement have generally been mild and dose-dependent, including muscle or joint aches, edema or tingling. There has been some concern about possible mitogenic effects of this therapy. It was noted that surveillance data from several studies have been largely reassuring, revealing no increase in the risk for de novo or recurrent tumor formation in patients on GH replacement. It was recognized that long-term data are mainly derived from studies of pediatric patients on GH replacement. It was again recommended that GH replacement be avoided in patients with active malignancy.
The safety of GH replacement in patients who have received radiation therapy to the central nervous system was recently evaluated in a retrospective study by Mackenzie and colleagues. Reassuringly, after a median follow-up period of 14.5 years, there was no increased risk for recurrent or secondary tumors in previously irradiated patients.
The possible adverse effects of GH replacement on glucose homeostasis have also raised some concern. In the Guidelines, it was noted that insulin resistance and hyperglycemia may occur in some patients receiving GH replacement. Particular attention to glucose monitoring was advised in patients with pre-existing diabetes.
Two large observational studies have recently examined the incidence of diabetes in adults on GH replacement. A study by Attanasio and colleagues analyzed data extracted from the HypoCCS surveillance database and found that the incidence of diabetes was not increased in US or European adults with hypopituitarism receiving GH replacement. On proportional hazard analysis, older age and higher BMI, but not GH replacement dose, predicted the risk for developing diabetes. In a study by Luger and colleagues, data from the KIMS surveillance database were reported, revealing an increased incidence of diabetes in adults on GH replacement. Higher BMI, older age and the presence of an adverse cardiometabolic risk profile at baseline (higher waist circumference, waist-to-hip ratio, systolic blood pressure, triglycerides and lower HDL cholesterol), but not GH replacement dose, were associated with higher risk for developing diabetes on GH replacement. These data suggest that glucose parameters be carefully monitored during GH replacement, particularly in patients at increased risk.
Recently published data by Carel and colleagues from the French arm of the SAGhE study raised new concerns about the long-term safety of GH replacement. Findings suggested that the mortality of adults who received GH therapy in childhood for isolated GHD, idiopathic short stature or born short for gestational age was increased in comparison with the general population. Patients at increased risk for death included those treated with GH doses >50 mcg/kg/day, which is higher than those currently recommended. Cause-specific mortality risk was increased for bone-related tumors, CVD and cerebral hemorrhage. However, the lack of an untreated control population and the incomplete ascertainment of some deaths make the interpretation of these data difficult.
In contrast, there was no mortality secondary to CVD or malignancy noted in another recent report in The Journal of Clinical Endocrinology & Metabolism by Savendahl and colleagues of SAGhE patients from three other European countries (Belgium, Netherlands and Sweden). Although these data indicate the need for ongoing long-term surveillance studies, they also suggest that GH has an excellent safety profile when used appropriately.
Our understanding of the benefits and risks of GH replacement therapy in adults continues to improve as a result of recent findings. Good clinical judgment is needed to maximize benefits while minimizing risk to adult patients receiving GH replacement therapy.
For more information:
- Attanasio AF. J Clin Endocrinol Metab. 2011;96:2255-2261.
- Carel JC. J Clin Endocrinol Metab. 2012;97:416-425.
- Jorgensen AP. Growth Horm IGF Res. 2011;21:69-75.
- Luger A. Diabetes Care. 2012;35:57-62.
- Mackenzie S. J Clin Endocrinol Metab. 2011;96:2756-61.
- Molitch ME. J Clin Endocrinol Metab. 2011;96:1587-1609.
- Savendahl L. J Clin Endocrinol Metab. 2012;97:E213-7.
- Spielhagen C. Growth Horm IGF Res. 2011;21:1-10.
- van Bunderen CC. J Clin Endocrinol Metab. 2011;96:3151-3159.
Disclosure: Dr. Tritos reports receiving research support and consulting fees from Pfizer.