Growth Hormone Replacement in Older Men

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http://www.emedicine.com/med/topic3178.htm

Growth Hormone Replacement in Older Men
Last Updated: July 15, 2005

Synonyms and related keywords: somatopause, hyposomatotropism of aging, adult growth hormone deficiency, GHD, GH, somatopause of aging, hyposomatotropism of aging, growth hormone-releasing hormone, GHRH, growth hormone-releasing peptide, GHRP, pituitary gland, hypopituitarism, insulin tolerance test, ITT


Author: Angela Gentili, MD, Director of Geriatrics Fellowship Program, Associate Professor, Department of Internal Medicine, Virginia Commonwealth University Health System & McGuire VAMC

Coauthor(s): Robert A Adler, MD, Chief, Endocrinology and Metabolism, McGuire Veterans Affairs Medical Center; Professor, Departments of Internal Medicine and Epidemiology and Community Health, Virginia Commonwealth University

Angela Gentili, MD, is a member of the following medical societies: American Geriatrics Society, and Virginia Geriatrics Society

Editor(s): Barry J Goldstein, MD, PhD, Director, Division of Endocrinology, Diabetes and Metabolic Diseases, Professor, Department of Internal Medicine, Thomas Jefferson University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Don S Schalch, MD, Professor Emeritus, Department of

Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics; Mark Cooper, MD, Head, Vascular Division, Baker Medical Research Institute; Professor of Medicine, Monash University; and George T Griffing, MD, Director, Division of General Internal Medicine, Professor, Department of Internal Medicine, St Louis University


INTRODUCTION


Background: Discussion in this article is limited to hyposomatotropism of aging. For more information on adult growth hormone deficiency (GHD), see Hypopituitarism (Panhypopituitarism).

The decrease in lean body mass and increase in adipose tissue that occurs with aging has been suggested to be partly due to the age-associated decrease in growth hormone (GH) and insulinlike growth factor-1 (IGF-1), also known as somatomedin C, which is produced by the liver and other tissues in response to GH. This decline in the secretory activity of the GH–IGF-1 axis has been termed somatopause or hyposomatotropism of aging. Whether this decrease in GH secretion should be treated is debatable.

Pathophysiology:

GH secretion

GH is released from the anterior pituitary gland in a pulsatile manner. Two hypothalamic hormones control GH secretion: Growth hormone-releasing hormone (GHRH) stimulates GH secretion, and somatostatin inhibits it. The majority of GH secretion occurs at night during slow-wave sleep, when somatostatin release is diminished.

GH stimulates production of IGF-1 in the liver and other tissues. IGF-1 circulates through the bloodstream bound to 6 specific binding proteins in several combinations. The major serum IGF-binding protein is insulinlike growth factor binding protein-3 (IGFBP-3). Both GH and IGF-1 have important metabolic actions in several tissues.

A single measurement of plasma GH levels is difficult to interpret because of the pulsatile secretion of GH. Levels of IGF-1 vary but little during the day; therefore, assays of IGF-1 have been used as a better indicator of the status of the GH–IGF-1 axis.

Effect of age on GH secretion

Several studies have shown that the amplitude of GH pulses is reduced with aging both in men and women. In aging men, GH secretion declines by 50% every 7 years after age 18-25 years. The negative effect of age on 24-hour mean serum GH is twice as much in men as in premenopausal women. Estrogens may have a protective effect that limits the rate of decline of GH secretion with aging.

IGF-1 and IGFBP-3 levels also decrease with aging. This decline of the GH–IGF-1 axis is probably caused by altered hypothalamic regulation (ie, decrease in GHRH and increase in somatostatin), rather than a decreased capacity to secrete GH.

The pathophysiology of the somatopause is confounded by several variables that can contribute to the decline in GH secretion associated with aging. These variables include the following:

* Adiposity: Individuals who are moderately to markedly obese have profound suppression of GH secretion at any age.

* Decreased production of sex steroid hormones: Falling levels of testosterone in men and estrogens in women affect GH secretion.

* Decreased physical fitness: A strong correlation exists between aerobic capacity and 24-hour serum GH concentration.

* Fragmented sleep: GH secretion can be affected by altered sleep patterns because it occurs predominantly during slow-wave sleep.

* Malnutrition: Poor nutritional status negatively affects IGF-1 synthesis and action.

Frequency:

* In the US: Incidence is unknown because somatopause may be part of normal aging rather than a disease.

Age: In aging men, GH secretion declines by 50% every 7 years after age 18-25 years.


CLINICAL

History: GHD in adults causes changes in body composition that are similar to those occurring with normal aging.

* Decrease in lean body mass

* Increase in total and abdominal fat

* Decrease in muscle strength

* Decrease in bone mineral density

Causes: The pathophysiology of somatopause is confounded by several variables that can contribute to the decline in GH secretion associated with aging: adiposity, decreased production of sex steroid hormones, decreased physical fitness, fragmented sleep, and malnutrition


DIFFERENTIALS

Hypopituitarism (Panhypopituitarism)
Obesity
Sleep Disorders


Other Problems to be Considered:

Malnutrition
Hypogonadism
Decreased physical fitness


WORKUP

Lab Studies:

* A single measurement of plasma GH levels is difficult to interpret because of the pulsatile secretion of GH. Levels of IGF-1 vary little during the day; therefore, assays of IGF-1 have been used as a better indicator of the status of the GH–IGF-1 axis. Plasma IGF-1 levels decrease with aging, and an inverse correlation exists between age and IGF-1 levels. A cutoff IGF-1 level cannot be used for diagnostic purposes because the GH–IGF-1 axis is influenced by other factors besides aging (see Pathophysiology). Furthermore, evidence of an association between IGF-1 levels and measures of muscle strength, body composition, and physical functioning in older adults is lacking. Hypotheses to explain this lack of association include the possibility that IGF-1 levels do not reflect GH status or that IGF-1 levels do not correlate with the biological activity of IGF-1.

* The insulin tolerance test (ITT) is the diagnostic test of choice to diagnose adult GHD. As long as adequate hypoglycemia is achieved, this test distinguishes GHD secondary to hypopituitarism from decreased GH secretion associated with aging or obesity. The ITT is contraindicated in patients with ischemic heart disease or seizure disorders, and many authorities prefer not to use the ITT in patients older than 60 years.

* In patients with contraindications to the ITT, alternative provocative tests can be used, although their diagnostic value is less established compared to the ITT. The most promising of these tests is the combined administration of arginine and GHRH; other alternatives include arginine alone, glucagon alone, or combination stimuli such as levodopa/carbidopa/propranolol. The clonidine test is less useful in adults than in children.


MEDICATION

GH replacement is effective in reversing many of the changes in lipids and body composition that occur in adults with GHD secondary to hypopituitarism. The effects of GH replacement in these patients include the following:

* Increase in lean body mass with reduction in fat mass

* Increase of bone mineral density of 4-10% above baseline after at least 12 months of treatment

* Increase in muscle strength with complete normalization after 3 years of treatment

* Reduction in serum total cholesterol, low-density lipoprotein cholesterol (LDL) and a decrease in LDL/HDL ratio.

* Improvement in psychological well-being and quality of life


Drug Category: Growth hormones -- Most studies of GH supplementation in healthy older people have shown that in both men and women, GH increases muscle mass and decreases body fat, but it does not improve strength. In a 6-month study, the combination of testosterone and GH also increased total body isotonic strength and aerobic capacity in older men. GH reduced serum leptin and LDL-C and increased triglycerides, with no effect on HDL. Common side effects were arthralgias and carpal tunnel syndrome.

One month of a small dose of GH (ie, 6.25 mcg/kg/d) alone or in combination with transdermal testosterone did not improve strength, flexibility, or percentage of body fat, but it improved certain measures of balance and physical performance in healthy older men. At such a small dose, there were no significant adverse events. In another study, GH did not enhance the positive effect of exercise on muscle strength.

GH secretagogues that would produce a more physiological increase in circulating GH levels are under investigation. These include GHRH and the growth hormone–releasing peptides (GHRPs) and their analogs. An orally active GH secretagogue, MK-0677, was studied in older adults with recent hip fractures. Although it increased serum IGF-1, it did not improve functional performance measures significantly.

GH treatment in frail older people

In a placebo-controlled trial of patients aged 64-99 years who were malnourished, GH caused a rise in circulating IGF-1, an average weight gain of 2.2 kg, and an increase in nitrogen retention. Older individuals are more sensitive to GH replacement than children and young adults; therefore, the dose of GH must be lower. Treating older adults with the amount of GH produced in healthy puberty (ie, 23-35 mcg/kg/d) can cause glucose intolerance, arthralgias, fluid retention, carpal tunnel syndrome, and rarely, papilledema.

Drug Name
Growth hormone; somatropin (Genotropin, Humatrope, Norditropin) -- hGH obtained by recombinant DNA technology. Amino acid sequence is identical to that of pituitary-derived hGH. Indicated in pediatrics to treat growth failure due to lack of adequate endogenous GH secretion, growth failure associated with chronic renal insufficiency up to the time of renal transplantation, and short stature associated with Turner syndrome. Indicated in adults to treat a biochemical diagnosis of adult GHD by means of a subnormal response to a standard GH stimulation test; patients who have adult GHD, either alone or with multiple hormone deficiencies (hypopituitarism) as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or patients who were GH deficient during childhood, confirmed as an adult before replacement therapy with somatropin is started.

Not FDA approved for older patients who do not meet the above criteria of adult GHD. Its use for hyposomatotropism of aging should be considered investigational. To minimize adverse effects in older and obese patients, lower doses may be necessary. During therapy, dosage should be decreased if required by the occurrence of adverse effects or excessive IGF-1 levels.

Adult Dose
GHD: 0.006 mg/kg/d SC initial; may increase to a maximum of 0.025 mg/kg/d in patients <35 y and to a maximum of 0.0125 mg/kg/d if >35 y
Hyposomatotropism of aging: 0.00625-0.02 mg/kg/d (optimal dose not known)

Pediatric Dose
GHD: Up to 0.30 mg/kg/wk SC divided into daily injections

Contraindications
Documented hypersensitivity; critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure; active neoplasia; growth promotion in pediatric patients with closed epiphyses (do not use)

Interactions
Excessive glucocorticoid therapy inhibits growth-promoting effect of somatropin; limited data indicate that GH administration increases CYP450-mediated antipyrine clearance in men; therefore, somatropin may alter clearance of corticosteroids, sex steroids, anticonvulsants, and cyclosporine

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Should be prescribed by physicians experienced in diagnosis and management of GHD, Turner syndrome, or chronic renal insufficiency; somatropin reduces insulin sensitivity; patients should be monitored for evidence of glucose intolerance; patients who are diabetic, obese, or have glucose intolerance should be monitored closely during GH therapy; patients with a history of intracranial lesion should be examined frequently for progression or recurrence; intracranial hypertension with papilledema, visual changes, nausea, and/or vomiting has been reported in a small number of patients (symptoms usually occur within the first 8 wk of initiation of GH therapy); in elderly individuals, dose selection should be cautious, starting at low end of dosing range; in pediatric patients, those with growth failure secondary to chronic renal insufficiency should be monitored periodically for evidence of progression of renal osteodystrophy; patients with scoliosis should be monitored for progression of scoliosis; patients with Turner syndrome should be monitored for otitis media, other ear disorders, and cardiovascular disorders


FOLLOW-UP

Complications:

* Adverse effects of GH replacement

o Carpal tunnel syndrome

o Gynecomastia

o Glucose intolerance

o Arthralgias

o Myalgias

o Peripheral edema

o Papilledema (rare)

Patient Education:

* For excellent patient education materials, see eMedicine's Growth Hormone Deficiency Center and the patient education articles Understanding Growth Hormone Deficiency Medications and Growth Hormone Deficiency FAQs.


MISCELLANEOUS

Medical/Legal Pitfalls:

* Providing GH supplementation to healthy older patients is a potential medicolegal pitfall.

Special Concerns:

* In conclusion, GH replacement in healthy older men improves body composition but not strength. Concomitant use of testosterone in older men may provide additional benefits (increased isotonic strength). The adverse effects of GH limit its use in older subjects.

* Whether reversing the age-associated decrease in GH secretion provides long-term benefit is not clear. Also unclear is whether an evaluation of the GH–IGF-1 axis is important to identify subjects who benefit the most and which older subjects (healthy or frail) benefit the most.

* Long-term studies are needed to clarify the role of GH and GH secretagogues as hormone replacement therapy for the hyposomatotropism of aging.


BIBLIOGRAPHY

# Bach MA, Rockwood K, Zetterberg C, et al: The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture. J Am Geriatr Soc 2004; 52: 516-523[Medline].
# Blackman MR, Sorkin JD, Munzer T et al: Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 2002 Nov 13; 288(18): 2282-92[Medline].
# Boguszewski CL, Meister LH, Zaninelli DC, Radominski RB: One year of GH replacement therapy with a fixed low-dose regimen improves body composition, bone mineral density and lipid profile of GH-deficient adults. Eur J Endocrinol 2005 Jan; 152(1): 67-75[Medline].
# Borst SE: Interventions for sarcopenia and muscle weakness in older people. Age Ageing 2004; 33: 548-555[Medline].
# Brill K, Weltman A, Gentili A, et al: Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men. J Clin Endocrinol Metab 2002; 87: 5649-57[Medline].
# Carroll PV, Christ ER, Bengtsson BA, et al: Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 1998 Feb; 83(2): 382-95[Medline].
# Elgzyri T, Castenfors J, Hagg E, et al: The effects of GH replacement therapy on cardiac morphology and function, exercise capacity and serum lipids in elderly patients with GH deficiency. Clin Endocrinol (Oxf) 2004 Jul; 61(1): 113-22[Medline].
# Genentech Inc: Nutropin (R) [somatropin (rDNA origin) for injection] prescribing information. Available at: http://www.genentech.com/gene/index.jsp[Full Text].
# GRS: Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 1998 Feb; 83(2): 379-81[Medline].
# Harman SM, Blackman MR: The Effects of Growth Hormone and Sex Steroid on Lean Body Mass, Fat Mass, Muscle Strength, Cardiovascular Endurance and Adverse Events in Healthy Elderly Women and Men. Horm Res 2003; 60: 121-124[Medline].
# Harman SM, Blackman MR: Use of growth hormone for prevention or treatment of effects of aging. J Gerontol A Biol Sci Med Sci 2004; 59: 652-8[Medline].
# Haydar ZR, Blackman MR, Tobin JD, et al: The relationship between aerobic exercise capacity and circulating IGF-1 levels in healthy men and women. J Am Geriatr Soc 2000 Feb; 48(2): 139-45[Medline].
# Kaiser FE, Silver AJ, Morley JE: The effect of recombinant human growth hormone on malnourished older individuals. J Am Geriatr Soc 1991 Mar; 39(3): 235-40[Medline].
# Kiel DP, Puhl J, Rosen CJ, et al: Lack of an association between insulin-like growth factor-I and body composition, muscle strength, physical performance or self-reported mobility among older persons with functional limitations. J Am Geriatr Soc 1998 Jul; 46(7): 822-8[Medline].
# Papadakis MA, Grady D, Black D, et al: Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Intern Med 1996 Apr 15; 124(8): 708-16[Medline].
# Rudman D, Feller AG, Nagraj HS, et al: Effects of human growth hormone in men over 60 years old. N Engl J Med 1990 Jul 5; 323(1): 1-6[Medline].
# Veldhuis JD, Iranmanesh A, Weltman A: Elements in the pathophysiology of diminished growth hormone (GH) secretion in aging humans. Endocrine 1997 Aug; 7(1): 41-8[Medline].