GH Research Society [1] and Endocrine Society Clinical Practice Guidelines [2] recommend dosing GH independent of body weight, starting with a low dose, then gradually increasing this to the minimal dose that normalizes serum IGF-I levels and improves symptoms, without causing unacceptable side effects. The high degree of inter-individual variability in both subcutaneous GH absorption and GH sensitivity makes this individualized, stepwise upward titration method preferable to standard weight-based dosing strategies (see below).[3]
Body weight-based GH dosing in adults was initially adopted from pediatric practice, but turned out to be supra-physiological and cause numerous side effects. Consequently, dosages were reduced, resulting in fewer adverse effects (most adverse effects are dose related).[4, 5] The most common acute (fast-onset) side effects (occurring in 5-18% of patients) are related to fluid retention and include paresthesia (a sensation of tingling, tickling, pricking, or burning in the skin), joint stiffness, peripheral edema, joint pain (arthralgia), and muscle pain (myalgia). People who are older and obese tend to be more prone to develop these complications.[6] With individualized dose-titration, compared to weight-based dosing, these side effects are less than half as frequent.[4] We will cover safety issues pertaining to diabetes, tumor regrowth/recurrence and cardiovascular morbidity in an upcoming article.
What follows below is a summary of the American Association of Clinical Endocrinologists (AACE) [3] and Endocrine Society [2] clinical practice guidelines for GH replacement therapy in adults with growth hormone deficiency.
NOTE: Growth hormone is measured in IU (international units) and mg (milligrams):
1 mg = 3 IU
1 IU = 0.33 mg
Starting dose:
• Age below 30 years:
1.2 – 1.5 IU per day (0.4 – 0.5 mg/day) (may be higher for patients transitioning from pediatric treatment)
• Age 30-60 years:
0.6 – 0.9 IU per day (0.2 – 0.3 mg/day)
• Age over 60 years:
0.3 -0.6 IU per day (0.1-0.2 mg/day)
Patient with diabetes or who are susceptible to insulin resistance / glucose intolerance should use the lowest starting dose (0.3 -0.6 IU per day) regardless of age.
Subcutaneous injections are usually administered in the evening to mimic physiologic nocturnal GH secretion.
Dose escalation (titration):
At 1- to 2-month intervals, increase dose in increments of 0.3 -0.6 IU per day (0.1-0.2 mg/day) based on clinical response, blood IGF-1 levels, side effects, and individual considerations such as insulin resistance / glucose intolerance.
Longer time intervals and smaller dose increments may be necessary in older patients.
Goal with GH treatment:
Aim for blood IGF-I levels in the middle of the normal range appropriate for age and sex, unless side effects are significant. Consider a trial of higher GH doses to determine whether this provides further benefit as long as the serum IGF-I levels remain within the normal range and the patient does not experience side effects.
Monitoring:
While IGF-1 levels are not a good indicator of GH status, the usefulness of IGF-1 for monitoring treatment of GH disorders in adulthood is now widely accepted, especially as GH-dosing regimens for growth hormone deficiency have evolved from weight-based dosing (associated with overtreatment and side effects) to individualized dose-titration strategies, which maintain IGF1 within target limits.[7]
At 6-month intervals once maintenance doses are achieved. Monitoring should include clinical evaluation and assessment of side effects, blood IGF-1, fasting blood glucose levels, and T3, T4 and free T4, as well at lipid profile. Quality of life measurements may be done every 6 or 12 months.
Patients on concurrent thyroid, sex hormone or glucocorticoid treatment may need dose adjustments after starting GH replacement therapy.
Factors that may cause a need for higher GH doses:
• Young patients regardless of onset type
• Low blood IGF-1 levels
• Addition of oral estrogen
• Change from transdermal to oral estrogen
• To induce breakdown of stored body fat (lipolysis)
Factors that may cause a need for lower GH doses:
• Elderly patients
• High blood IGF-1 levels
• Discontinuation of oral estrogen
• Change from oral to transdermal estrogen
• Co-treatment with testosterone
• Elevation in fasting blood glucose and/or HbA1c (i.e. worsening glucose tolerance)
• Side effects
Comments
An important issue is whether GH treatment should be continued throughout life. There are no hard-fast rules on this. With the exception of estrogen after the menopause, most other pituitary replacement hormones (e.g. thyroid hormone and testosterone) are given indefinitely. When it comes to GH treatment, if patients on report significant quality of life benefits and/or there are objective improvements in in cardiovascular risk markers, body composition, physical activity tolerance, and bone mineral density (assessed by DEXA) then GH treatment should be continued indefinitely. But if no apparent or objective benefits of treatment are achieved after at least 2 years, discontinuing GH therapy may be considered. If patients decide to discontinue GH replacement therapy, a 6-month follow-up appointment should be offered, because a substantial number of patients may wish to resume therapy, noting in retrospect that they did feel better on treatment. Body composition and fat distribution changes (especially waist circumference), as well as metabolic parameters, should also be tracked during and after GH treatment discontinuation in order to get an objective indication of GH treatment effects.
It is noteworthy that there are few data regarding the ideal target for blood IGF-1 level. Until further data become available to address whether IGF-1 levels should be targeted at the middle versus the upper half of the reference range for maximum benefit, the American Association of Clinical Endocrinologists guidelines recommend targeting IGF-1 levels at the middle of the reference range quoted by the laboratory utilized.[3] However, the exact IGF-1 target should ultimately be based on the circumstances and complete clinical picture of each patient. As we have described in previous blog posts, monitoring IGF-1 is important as both too low and to high IGF-1 levels may be dangerous. For more info, see:
What’s the relation between IGF-1 and Cancer?
Association of IGF-1 (Insulin-Like Growth Factor-1) with Mortality, Cardiovascular Disease, and Cancer
Premenopausal and postmenopausal women taking estrogen HRT need a higher dose than men in order to achieve a given IGF-1 level because estrogen attenuates GH action.[8-11] And even with higher doses than men, the effects of GH on body composition, especially fat loss, may be blunted in women.[12]
Men who are on testosterone replacement therapy may need a lower GH dose because testosterone increases GH and IGF-1 production, especially in older men.[13-15] Testosterone treatment also restrains the dose-dependent feedback inhibition of IGF-1 on pulsatile growth hormone secretion.[16] We will be cover this in more depth in an upcoming article. Testosterone and GH seem to work beneficially together; testosterone boosts the GH/IGF-1 axis, and treatment with GH augments the effects of testosterone on gains in total and leg/arm lean mass, muscle strength, and aerobic endurance, as well as reductions in whole-body and trunk fat. We covered this in more detail in a previous article “Combined Testosterone and GH therapy for best results on body composition and safety profiles”. Thus, it seems that GH and testosterone work together and allow for achievement of beneficial effects at lower doses, compared to treatment with either alone.[17]
We will cover the interaction between growth hormone and sex steroids (testosterone and estrogen) in an upcoming article…stay tuned!
References:
1. Ho, K.K. and G.H.D.C.W. Participants, 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(6): p. 695-700.
2. Molitch, M.E., et al., Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2011. 96(6): p. 1587-609.
3. Cook, D.M., et al., The American Association of Clinical Endocrinologists Medical Guidelines for Growth Hormone use in Growth Hormone Deficient Adults and Transition Patients – 2009 Update. 2009.
4. Hoffman, A.R., et al., Efficacy and tolerability of an individualized dosing regimen for adult growth hormone replacement therapy in comparison with fixed body weight-based dosing. J Clin Endocrinol Metab, 2004. 89(7): p. 3224-33.
5. Kehely, A., et al., Short-term safety and efficacy of human GH replacement therapy in 595 adults with GH deficiency: a comparison of two dosage algorithms. J Clin Endocrinol Metab, 2002. 87(5): p. 1974-9.
6. Holmes, S.J. and S.M. Shalet, Which adults develop side-effects of growth hormone replacement? Clin Endocrinol (Oxf), 1995. 43(2): p. 143-9.
7. Mukherjee, A. and S.M. Shalet, The value of IGF1 estimation in adults with GH deficiency. Eur J Endocrinol, 2009. 161 Suppl 1: p. S33-9.
8. Leung, K.C., et al., Estrogen regulation of growth hormone action. Endocr Rev, 2004. 25(5): p. 693-721.
9. Ho, K.K., et al., Regulating of growth hormone sensitivity by sex steroids: implications for therapy. Front Horm Res, 2006. 35: p. 115-28.
10. Meinhardt, U.J. and K.K. Ho, Modulation of growth hormone action by sex steroids. Clin Endocrinol (Oxf), 2006. 65(4): p. 413-22.
11. Veldhuis, J.D., et al., Testosterone and estradiol regulate free insulin-like growth factor I (IGF-I), IGF binding protein 1 (IGFBP-1), and dimeric IGF-I/IGFBP-1 concentrations. J Clin Endocrinol Metab, 2005. 90(5): p. 2941-7.
12. Burman, P., et al., Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. J Clin Endocrinol Metab, 1997. 82(2): p. 550-5.
13. Gentili, A., et al., Unequal impact of short-term testosterone repletion on the somatotropic axis of young and older men. J Clin Endocrinol Metab, 2002. 87(2): p. 825-34.
14. Veldhuis, J.D., et al., Testosterone supplementation in healthy older men drives GH and IGF-I secretion without potentiating peptidyl secretagogue efficacy. Eur J Endocrinol, 2005. 153(4): p. 577-86.
15. Muniyappa, R., et al., Long-term testosterone supplementation augments overnight growth hormone secretion in healthy older men. Am J Physiol Endocrinol Metab, 2007. 293(3): p. E769-75.
16. Veldhuis, J.D., et al., Testosterone supplementation in older men restrains insulin-like growth factor’s dose-dependent feedback inhibition of pulsatile growth hormone secretion. J Clin Endocrinol Metab, 2009. 94(1): p. 246-54.
17. Giannoulis, M.G., et al., Hormone replacement therapy and physical function in healthy older men. Time to talk hormones? Endocr Rev, 2012. 33(3): p. 314-77.
