Indian Journal for the Practising Doctor

Kalra S

Dr. Sanjay Kalra,
Bharti Hospital, Karnal, India 132001
[E mail: bhartihospital(at)rediffmail.com]

ISSN: 0973-516X

The rapid increase in the number of elderly people, secondary to a prolonged life expectancy due to improved medical care, has led to heightened interest in the geriatric medicine. During the last half-century, the average life span has increased by 20 years, and is expected to rise another 10 years by 2050¹. The global population ≥65 years in age will grow from 420 million to 973 million between 2000 and 2030².

The average individual is more concerned than before about his health, and geriatric citizens demand independence, mobility and activity. Discussion about ‘healthy aging’ and about the utility of hormonal supplementation to ensure a youthful old age is needed. This review deals with the role, advantages and limitations of growth hormone supplementation in the elderly population.

Clinical features of growth hormone deficiency in the elderly Growth hormone deficiency (GHD) is a clinical, metabolic syndrome with many nonendocrine manifestations. These include:^3–13

1. Change in body composition
   • increased total fat mass
   • central obesity
   • decreased lean body mass
2. Change in bone metabolism
   • decreased bone mass
   • increased fraction rate
3. Insulin resistance
   • increased fat mass
   • dyslipidemia
   • premature atherosclerosis
4. Cardiac dysfunction
   • impaired diastolic function
   • impaired systolic function(controversial)
5. Change in quality of life
   • decreased well being
   • increased social isolation
   • decreased energy

Elderly patients present with similar symptoms, especially reduced quality of life and asthenia. Growth hormone deficiency should be suspected in patients with catabolic symptoms or those in whom one feels anabolic therapy is required.

Growth hormone physiology in the elderly Growth hormone secretion declines with aging by 15-70%^14,15. This decline is associated with an increase in total body fat of 9-18% in men and 12-13% in women,^16,17 localized to the intra-abdominal compartment, rather than subcutaneous fat.¹⁸ An actual reduction in subcutaneous fat in the thigh occurs with aging.¹⁹

A gradual, age-dependent reduction in bone mineral density and lean body mass also occurs with age^17,19,20. When expressed as ‘relative’ muscle mass, the decline in skeletal muscle mass occurs from third decade onwards, but when reported as ‘absolute’ muscle mass, the fall is evident only after age 45. At this time, changes begin occurring in muscle fibre crosssectional area, body cell mass and strength²¹.

By age 80, an average male will lose about 7 kg of muscle mass, while an average female will lose 3.8 kg²¹. This is associated with a reduction in the lower extremity strength of up to 50% by this age²⁴.

This loss of muscle mass and function (sarcopenia) leads to physical frailty, weakness and decreased physical activity. The resultant decreased mobility causes disability and loss of independence²⁵.

The reasons for sarcopenia include a large number of contributory factors^26-33, such as loss of alpha-motor neurons; dietary protein deficiency; reduced physical activity; increase in interleukin-6, tumor necrosis factor-α, interleukin-15, and ciliary neutrotrophic factor-1; decrease in insulin-like growth factor-1 (1GF-1); and changes in voltage-gated Ca2 and K+ ion channels.

Sacropenia, therefore, may be a potential target for those wishing to improve quality of life in the aged patients. Similarly, the changes in body composition and physiology that occur with aging may be targeted to improve ability and independence in geriatric patients.

Growth hormone therapy in the elderly: the rationale^14,16

1. There is an age-dependent decline in growth hormone and IGF-1.
2. The age-dependent changes in body composition/physiology are similar to those noted in adult growth hormone deficiency (AGHD)
3. Growth hormone supplementation in patients with AGHD improves body composition, body physiology and quality of life.
4. Hence, growth hormone therapy should be effective in otherwise healthy, elderly subjects.

Effect of growth hormone supplementation Growth hormone replacement in patients with AGHD improves quality of life, as documented in many studies^34,35. Withdrawal of the hormone therapy also results in negative psychologic effects³⁵.

Positive effects on memory have been found in animals treated with growth hormone. These effects are mediated through an increase in endogenous glutathione, which reduces oxidative stress in the hippocampus, where GH receptors are present.³⁶

Growth hormone supplementation in healthy older male adults aged >60 years over 6 months with 0.03mg/kg/wk given SC, 3 times a week, increased lean body mass, bone density at the spine, and decreased the fat mass.³⁷ Similar results were found in a group of 52 men older than 69 years, treated for the same duration with the same dose.

A shorter (10 week long) study in 18 healthy elderly men demonstrated positive effects on body composition when GH treatment (0.02mg/kg/day) was combined with muscle strength training.³⁸

Beneficial effects have been noted in postmenopausal women given a combination of growth hormone, diet and exercise therapy. An enhanced loss of truncal fat rather than peripheral fat was achieved, as compared to the placebo group.³⁹

Growth hormone, given in combination with testosterone, has synergistic anabolic action. Total body strength, VO2 max, and protein synthesis increased in men older than 65 years, who received the two hormones for 26 weeks⁴². However, similar results were not achieved in women given growth hormone and estrogen together.

In another study, growth hormone and testosterone combination therapy was compared with both hormones given as monotherapy, in healthy men aged 65 to 80 years. The lean body mass and strength of knee extension increased with the combination therapy.⁴³

Potential risks of growth hormone One potential risk of the exogenous growth hormone therapy is malignancy. The antiapoptotic effect of growth hormone/1GF-1, coupled with the proliferative effects of 1GF-1, in the presence of genetically-damaged cells, could increase the risk of cancer.

However, no increase in de novo neoplasia or re-growth of primary pituitary tumours has been seen in children or adults. Review of current data emphatically shows that the growth hormone is safe and does not lead to tumorigenesis in the growth hormone- deficient adults^44-46.

Another potential risk is diabetes mellitus, as growth hormone is counter regulatory to insulin. However, only two cases of reversible diabetes have been reported in a series of 400 adults treated with growth hormone. It has been documented that growth hormone has beneficial effect at 1 year, and no effect at 7 years, on insulin sensitivity.^46,47

Other side effects such as edema, carpal tunnel syndrome and joint pains are dose dependent, and reverse on dose reduction. No major side effects, therefore, limit the utility of growth hormone in the elderly.

Clinical investigations

Concomitant pituitary hormone deficiencies should be investigated for, identified and corrected before initiating growth hormone in the elderly. Incipient adrenal insufficiency and central or secondary hypothyroidism should be ruled out, or corrected prior to the therapy. Baseline estimation of lipid, glucose and other metabolic parameters is necessary. Ideally, this assessment should include investigations for osteoporosis and psychological well being. Body composition can be checked by determining weight, body mass index, waist and hip circumferences, and skin fold thickness. If available, bio-impedance assessment (BIA) or dual energy x-ray absorptiometry (DEXA) can be performed to assess lean mass and fat distribution.⁴⁸

Dose selection

Older, more obese patients with adult onset growth hormone deficiency are more sensitive to growth hormone than younger, leaner patients, or those with childhood-onset deficiency.⁴⁹ Men are more sensitive to the effects of growth hormone, with regards to body composition, lipid profile, and bone turnover markers, than women.⁵⁰ Women receiving oral estrogens are more resistant to growth hormone in serum insulin-like growth factor-1 response, and develop less edema or fluid retention.⁵¹ Dose selection thus depends on clinical and biological response markers, and should be individualized

Dose titration

The initial dose in elderly patients is 0.1 mg/day, but speed of titration will vary from person to person. Response can be assessed clinically, by quality of life, or serum IGF-1. This is a more sensitive marker of the growth hormone, and is more appropriate as a dose titration tool than serum GF binding prtein-3 (1GFBP-3) and acid-labile subunit (ALS). IGF-1 response to growth hormone reflects the hepatic effect of the drug, and mediates many of the anabolic and metabolic effects.⁵³ It cannot be used as a surrogate marker for other efficacy variables, Other parameters to monitor efficacy of growth hormone include BIA, which can measure changes in extra cellular water (ECW) compartment.⁵⁴

In the absence of these parameters, one can monitor therapy by watching for side effects such as fluid retention, weight gain or edema.

The mean dose of growth hormone at 1 year was 0.45 mg/d when titrated vis-à-vis an individualized dose regime based on serum IGF- 1, body composition and clinical response.

When dose titration was weight-based, the mean dose was 0.55 mg/day, but the incidence of side effects was 70%, as compared to only 30% in the individualized dose-titration group.⁵⁵

In another study, median maintenance doses were 0.27mg/day in men and 0.4mg/day in women when titration was done against serum 1GF-1 levels, aiming for an 1GF-1 level in the upper half of age specific reference ranges.⁵⁶

The optimal approach is to commence treatment at a low dose, and titrate upward depending on a response of growth hormonedependent variables.

Quality of life can be used as an endpoint to titrate growth hormone doses, but no studies have been done to confirm this. It has been documented, however, that many beneficial effect of the treatment are noted only after 6 months. The onset of effects may be delayed in patient receiving low initial doses of the drug.⁵⁷

This means that therapy should be continued for an adequate period of time before making judgements on the effects on quality of life or psychological well being.

Long term replacement of growth hormone has been carried out for up to 10 years.⁵⁸ These studies show improvement in bone mineral content⁵⁹ (9%), bone mineral density, muscle strength and muscle function.⁶⁰ It reduces intima media thickness, a marker for atherosclerosis.⁶¹

Recommendations

As of today, no strong data exists to recommend growth hormone supplementation in healthy elderly subjects. However, the data available does permit use of this hormone, in low doses, under controlled conditions, in individual geriatric patients, where sacropenia seems to be a major factor for frequent falls, fractures, disability and loss of independence.

Conclusion

Low dose growth hormone, used cautiously, can improve the metabolic health and quality of life of elderly people. This field of medicine needs to be studied in greater detail, as our growing geriatric population expects better care and a healthier, more independent old age.

The future should see more frequent utilization of this, as well as other anabolic treatment modalities, in elderly persons wishing to enjoy better, more active and productive lives.

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