Management of Adult Growth Hormone Deficiency: Safe and Effective

Abstract

Progressive pituitary hormone deficiency is characteristic of aging, and the hypothalamic-GH-IGF-I axis is the first hormonal system affected. Daily GH secretion peaks around puberty, begins to decline by age 21, and by age 60, most adults have total 24-hour GH secretion rates indistinguishable from those of hypopituitary patients with organic lesions in the pituitary gland. Aging adults, even those receiving hormone replacement therapy with DHEA, thyroxine and sex steroids, frequently still report fatigue, lethargy, and decreased strength and exercise tolerance. Several recent epidemiologic studies indicate increased risk of cardiovascular morbidity and mortality in this population. A significant body of research suggests adult GH deficiency (AGHD) plays a key role in these age-associated health issues, and that therapy that restores GH to mid-normal ranges can successfully and safely ameliorate them. This article summarizes key studies documenting AGHD syndrome, the beneficial effects of GH therapy, the question of whether promoting activity in the GH-IGF axis increases risk of cancer and insulin resistance, and the efficacy of oral GH-releasing agents.

Adult Growth Hormone Deficiency

Progressive pituitary hormone deficiency is characteristic of aging, and the first hormonal system affected is the hypothalamic-GH-IGF-I axis. Daily growth hormone (GH) secretion peaks around puberty, beginning to decline by age 21. By age 60, somatopause is fully evident; most adults >60 have total 24-hour GH secretion rates indistinguishable from those of hypopituitary patients with organic lesions in the pituitary gland.¹ Aging adults, even those receiving hormone replacement therapy with DHEA, thyroxine and sex steroids, frequently still report fatigue, lethargy, and decreased strength and exercise tolerance. Several recent epidemiologic studies indicate increased risk of cardiovascular morbidity and mortality in this patient population.^{2 3 4 5 6 7} A significant body of clinical evidence suggests GH deficiency plays a key role in these age-associated health issues.

An adult GH deficiency (AGHD) syndrome has been documented, consisting of deleterious alterations in body composition (increased visceral adipose tissue, sarcopenia, and decreased bone mineral density), an atherogenic lipid profile, decreased muscle strength and aerobic capacity, low energy, apathy, and greatly decreased quality of life.⁸

Over the past 15 years, a large body of clinical evidence has identified AGHD as an important cause of aging-associated hypopituitary syndrome and demonstrated that GH therapy is effective in ameliorating all related symptoms. GH therapy has been shown to decrease fat mass, increase lean body mass, increase bone mineral density, reduce both LDL and total cholesterol, reduce carotid-artery intimal media thickness, increase the number and function of endothelial progenitor cells (which repair the vascular wall), increase exercise tolerance, and dramatically improve overall quality of life.^{8 9 10}

Cognition Effects of Growth Hormone

Interest in the use of GH to improve quality of life in aging adults also stems from research reporting that the GH/IGF-I axis exerts neuroprotective and neurostimulating effects that bolster cognition and memory in the aging brain. A secondary analysis of a prospective cohort of 460 U.S. male physicians (mean age 57) participating in the Physicians’ Health Study II found that higher midlife free IGF-I was associated with significantly better late-life cognition.¹¹ A second prospective study involving 590 women aged 60-68 years produced similar results, as did an Italian study of 353 elders 80 years or older, which found lower levels of serum free IGF-I were strongly associated with impaired cognitive performance.^{12 13} In a placebo-controlled trial, 6 months’ of treatment with daily growth hormone releasing hormone (GHRH) significantly improved cognition in healthy older (average age 68) adults.¹⁴

In animal studies, GH treatment of old rats improves brain vascularity, regional brain blood flow and cognitive function, thus reducing and even reversing the effects of aging on the CNS. Administration of GHRH (to increase endogenous release of GH and thus endogenous IGF-I levels) or direct administration of IGF-I have both been shown to reverse the age-related decline in spatial working and reference memory.^{15 16}

Plasticity in the CNS involves the functional interplay between the three major cell types: neurons, astrocytes, and oligodendrocytes. GH and IGF-I beneficially affect all three. In addition to the neuroprotective effects of GH and IGF-I shown in experimental models of CNS injury, IGF-I increases progenitor cell proliferation and new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus.¹⁷

The cerebral vasculature is an important paracrine source of IGF-1 for the brain, but microvascular density on the brain’s surface decreases with age. Low numbers and dysfunction of endothelial progenitor cells, resulting in insufficient repair of damaged vascular walls, is a significant factor, not only in decline in brain function but in the increased risk of atherosclerosis associated with aging. In middle-aged and elderly human subjects, treatment with GH reverses age-related endothelial progenitor cell dysfunction, suggesting that GH treatment may help to maintain cerebral vasculature and reduce risk of atherosclerosis.¹⁸

GH-induced increases in IGF-I levels may explain the increase in cerebral arteriole density observed after GH treatment and the ability of GH therapy to enhance cognitive functions, including memory. Recent findings indicate GH secretagogues also exert neuroprotective effects and effects on synaptic plasticity.^{19 20}

Gender Affects Response to GH Therapy

In some studies, the beneficial effects of GH therapy have been more pronounced in men than in women, indicating a sexually dimorphic response to GH therapy. Women on oral estrogen replacement therapy, regardless of whether bio-identical equine estrogens are used, are relatively resistant to GH and require higher doses to raise IGF-I levels to those producing salutary effects in men.⁸

Could GH Therapy Increase Risk of Cancer? Diabetes?

It has been questioned whether the age-related decline in the activity of the hypothalamic-GH-IGF axis may be a protective mechanism against the development of cancer and insulin resistance.²¹

GH and Cancer

Regarding GH and cancer, the data are limited and conflicting. GH, via its mediator peptide IGF-I, is involved in the regulation of cell growth and could promote an anti-apoptotic environment, thus increasing risk for the survival of genetically damaged cells. A recent meta-analysis reviewing 21 studies that rigorously examined the relationship between cancer and endogenous IGF-I levels in normal subjects found a significant link between IGF-I levels within the highest quartile of the normal range and prostate and premenopausal breast cancers, but no association with lung, colorectal, or postmenopausal breast cancer. [Emphasis added to underscore that no association was found between IGF-I levels in the three lower quartiles and cancer risk.]²²

Some epidemiological studies of patients with acromegaly suggest an increased risk of colorectal cancer, while others indicate no increase in cancer incidence in individuals with acromegaly or in another group in which risk would be thought to be heightened: cancer survivors. Extensive studies of the outcome of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk.^{23 24}

The authors of a recent review entitled, “Does growth hormone cause cancer?” conclude, “Finally, even if GH/IGF-1 therapy does result in a small increase in cancer risk compared to untreated patients with GH deficiency, it is likely that the eventual risk will be the same as the general population. Such a restoration to normality will need to be balanced against the known morbidity of untreated GH deficiency.”²⁵

GH and Insulin Resistance

Although GH has well established anti-insulin actions, and chronic elevation of GH produces insulin resistance in humans, the lipolytic action of injected GH can initially improve sensitivity to insulin, suggesting that daily dosing should be avoided.²⁶ Less frequent dosing not only minimizes risk of insulin resistance, but has been shown to be just as effective. In AGHD patients, GH replacement therapy given 3 times weekly in doses resulting in serum IGF-I concentrations in the mid-normal range of adults ranging in age from 25-35 has been shown to be just as effective as daily dosing in improving lipid profile, body composition, bone mass and turnover, and to reverse cardiovascular abnormalities.^{27 28}

Given the important role of adipocytes in producing insulin resistance, the effect of GH or GH releasing agents on insulin may also be counterbalanced by the inverse relationship between GH levels and visceral adiposity in older individuals. In addition, clinical trials have shown that administration of recombinant human (rh)-IGF-I improves insulin sensitivity and hyperglycemia in patients suffering from type 1 and type 2 diabetes mellitus, as well as severe insulin resistance.²⁹ Thus, while chronic, daily GH injections may promote insulin resistance, the use of GH releasing agents, or even GH, several times a week is unlikely to do so.

Are Oral GH Releasing Agents Effective?

Yes, oral supplementation with amino acids (primarily the combination of arginine and lysine) has been conclusively shown to induce GH release; however, pre-exercise oral supplementation with amino acids proven to be capable of inducing GH release does not further heighten the exercise-induced release of GH.³⁰

A number of studies have confirmed that oral ingestion of specific amino acids stimulates GH release:

Ingestion of 1.5 g of arginine plus 1.5 g of lysine by young men under basal conditions increased plasma GH concentrations 2.7-fold at 60 minutes postconsumption, although ingestion immediately before resistance exercise did not further augment exercise-induced secretion of GH.³¹

Ingestion of 1.2 g of arginine plus 1.2 g of lysine by young men increased plasma GH concentrations within 30 min, with peak GH concentrations nearly 8-fold greater 90 minutes after ingestion. The phenomenon was reproducible, and the GH secreted had biological activity (demonstrated by somatomedin induction), but the combination was essential. When used singly, neither arginine (1.2 or 2.4 g), nor lysine (1.2 g) affected plasma GH concentrations.³²

Ingestion of 2 g of glutamine after a light breakfast increased plasma GH concentration 4.3-fold in subjects aged 32- to 64 years 90 min after consumption. Conditions were selected to be those that would normally result in minimal GH secretion in a population of age-dependent low secreters. Results were reproducible. It is thought that glutamine acted indirectly through conversion to arginine. Glutamine conversion to citrulline in the small intestine supports renal arginine synthesis, a known stimulus for GH secretion.³³

Administration of a lysine-arginine combination (the commercial preparation Lysargin, Baldacci, Italy) to elderly individuals and cancer patients has been shown to increase the synthesis and/or release of thymulin to values comparable to those recorded in young, healthy subjects. Researchers note this effect is mediated through “the known secretagogue activity of the amino acids on the pituitary release of growth hormone, which has a modulating effect on the thymic endocrine activity.”{ref34, ³⁵

Oral ingestion of GABA may even augment the exercise-induced increase in GH levels. In a randomized, double-blind, placebo-controlled trial, resistance trained men (n=11) aged 18-30 years, ingested either 3 g of GABA or sucrose placebo. At rest, GABA elevated GH concentrations about 400%. The combination of GABA and resistance exercise resulted in an additional 200% increase in GH concentrations beyond that seen without exercise.³⁶

Conclusion

More than a decade’s worth of controlled clinical trials confirm the existence of a distinct AGHD syndrome and the ability of treatment that restores GH to a mid-normal range to amend many of its symptoms safely and effectively—without increasing risk of cancer, insulin resistance or diabetes. The effects of GH and IGF-I treatment in older individuals indicate that amelioration of the age-related decline in the activity of the somatotropic axis can improve body composition, decreasing fat mass while increasing lean body mass and bone mineral density; promote cardiovascular health via reducing LDL and total cholesterol and carotid-artery intimal media thickness, while increasing the number and function of endothelial progenitor cells; and increase exercise tolerance and cognition, dramatically improving overall quality of life—clinical objectives highly likely to be desired by most aging individuals. Issues that need to be addressed include choosing optimal GH-restoring agents that do not interfere with the body’s own production of or sensitivity to GH; lab testing that enables objective, careful monitoring of treatment to ensure dosing that results in serum IGF-I concentrations in the mid-normal range for a 25-35 year old male or female; and the development of a comprehensive treatment program that includes exercise and a health-promoting diet.

References