ABSTRACT

Growth hormone (GH) plays important roles in adult life, including maintaining lean and bone mass, promoting lipolysis to limit visceral adiposity, and regulating carbohydrate metabolism, cardiovascular function, aerobic exercise capacity, and cognitive function. Younger adults with growth hormone deficiency (AGHD) exhibit abnormalities in body composition, physical and cognitive function, and quality of life, which are reversed by GH replacement therapy. With advancing age, GH production declines, a phenomenon paralleled by physical and functional alterations similar to those observed in AGHD; however, the extent to which GH decline causes these age-related changes remains uncertain. Seemingly in opposition to the theory that the diminished GH secretion of older age is a net detriment are observations that animal models of congenital GH deficiency have remarkably increased lifespan, and that humans with congenital GH deficiency may have decreased rates of age-related diseases such as diabetes and cancer. Several short-term studies aiming to increase GH in older adults using a variety of interventions, including exercise, GH administration, or GH secretagogues, have demonstrated consistent effects on body composition but inconsistent effects on physical and cognitive function. While side effects of GH administration in older adults include edema, arthralgias, and elevated blood glucose, data regarding the possible long-term effects on risk of fractures, cancer, cardiovascular disease, life expectancy, and mortality are lacking. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

The decline in growth hormone secretion observed with aging is associated with changes in body composition and physical and psychological function. These are similar to those seen in younger adults with growth hormone deficiency. A decrease in night-time growth hormone secretion is associated with reductions in lean body mass and muscle strength. It also leads to increased body fat, particularly in the visceral compartment, decreased memory and cognitive function, decreased deep (slow-wave) sleep, and increased sleep disorders. Although these changes show only an association, and it remains unknown whether there is a causal link between them, they have led to speculation that replacing or stimulating growth hormone secretion may reverse some detrimental features of aging (1, 2).

AGE-RELATED CHANGES IN GROWTH HORMONE SECRETION

The trophic hormones that rise at puberty, including sex steroids and GH, have dramatic effects on body composition and strength. Their levels plateau in young adulthood and then decline. This decline is accompanied by a loss of skeletal muscle mass and aerobic capacity, and an increase in abdominal fat. These changes resemble some features of hypogonadism and adult GH deficiency (3).

After the third decade of life, GH secretion declines about 15% per decade. The GH half-life falls by 6%. At puberty, secretion peaks at about 150 µg/kg/day. By age 55, it drops to 25 µg/kg/day (4). The reduced 24-hour secretion is due mainly to a marked reduction in nocturnal GH pulse amplitude, with little change in pulse frequency or diurnal pattern (5). This secretory pattern shows disruption of the day-night GH rhythm due to the loss of nocturnal sleep-related GH pulses (5). Human GH circulates partially bound to two GH binding proteins: a high-affinity GH-BP binds 85-90% of circulating GH, and a low-affinity GH-BP binds the rest. GH-BPs decrease after age 60, potentially increasing the bioavailability of growth hormone (6). This decrease likely parallels the decline in growth hormone receptor levels with age, as the high-affinity GH-BP is identical to the extramembranous portion of the GH receptor. Although slow-wave sleep (SWS) decreases with age, most studies administering GH or GHRH to older adults did not improve SWS.

The liver is the main site of IGF-I production and is regulated by GH. IGF-I levels decline with age, mainly due to reduced GH secretion and not increased GH resistance. Studies in people with pituitary disorders and dose-response research show that older adults need lower GH doses to keep IGF-I normal. Older people are more sensitive to GH side effects and often have lower target IGF-I levels (7,8). IGF-I is present in blood and tissues, both free and bound to IGF-binding proteins (IGFBPs). IGF-I secretion is shown to reduce with aging (Figure 1) and that thereby reduces GH pulse amplitude and decreased overall GH production even though they maintained similar pulse frequency (9). IGFBP-3 is the major IGF-I binding protein. It binds 70-95% of circulating IGF-I in human plasma. Its synthesis depends on GH. IGFBP-3 also decreases with age in men from 22 to 79 years and is strongly associated with the decline of IGF-I (10).

FIGURE 1.

Serum IGF-I Levels vs. Age in Healthy Women and Men in the BLSA. From O’Connor, et al. J Gerontology A,1998, Vol 53, M176-82.

POTENTIAL MECHANISMS UNDERLYING THE DECLINE IN GH SECRETION WITH AGE

Three hypothalamic factors regulate GH secretion: somatostatin (Somatotropin Release-Inhibiting Factor, SRIF), growth hormone-releasing hormone (GHRH), and ghrelin (11) (Figure 2). Somatostatin noncompetitively inhibits GH and other hormone secretion. It modulates the GH response to GHRH. GHRH is the main stimulator of GH synthesis and release. Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor-1a (GHSR-1a). It is secreted mainly by the stomach and stimulates appetite independently of its effect on GH secretion. Recent preclinical data suggest that not all ghrelin effects are mediated by GHSR-1a (12). Its orexigenic and GH secretagogue actions do require GHSR-1a (13). Acylated ghrelin levels decline with age (14). Synthetic GH secretagogues (GHS) also activate GHSR-1a and strongly promote GH release.

A variety of stimuli and inhibitors affect hypothalamic factors that regulate GH production. These include exercise, sleep, food intake, stress, and body composition (15). All these factors interact to generate physiological patterns of pulsatile GH secretion.

FIGURE 2.

Major components of the GH neuroregulatory system. GH receptors are present in the liver, cartilage, muscle, adipose (fat), kidney, and other tissues. (GH, Growth Hormone; IGF-I, Insulin-like Growth Factor-I; FFA, Free Fatty Acids; GHRH. Growth Hormone Releasing Hormone; SST, Somatostatin).

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Several mechanisms could contribute to decreased GH secretion with age. These include reduced GHRH or ghrelin secretion, greater somatostatin inhibition, greater somatotroph sensitivity to IGF-I feedback, reduced pituitary responsiveness to GHRH, and reduced pituitary or hypothalamic responsiveness to ghrelin.

Whether the aging pituitary responds normally to GHRH and ghrelin is still a matter of debate. Although earlier studies suggest no age–related decline in GH responsiveness to GHRH, more recent reports indicate a gender-independent, age-related decline in acute GH responsiveness to GHRH and ghrelin (16). However, GH secretion can be restored by injection or infusion of GHRH, as well as by GHRH analogs or non-peptide GH secretagogues (2). There appears to be no age-related increase in GH sensitivity to IGF-I’s negative feedback (17); however, there may be a relative deficiency in GHRH and ghrelin secretion, and an increase in somatostatin secretion, in older individuals (18). The density of GHSR-1a receptors in the hypothalamus decreases with aging, and this is thought to be responsible for the age-related decreased response to some GHS’s (19). The aging pituitary is also less responsive to exercise, sleep, hypoglycemia, and other physiological stimuli. Based on these observations, it is most likely that the age-related change in GH secretion is multifactorial in etiology and is primarily caused by changes above the pituitary level.

GH SECRETION IN RELATION TO ADIPOSITY AND GONADAL STEROIDS

Obesity is associated with decreased GH secretion and responsiveness to secretagogues. Both increased adiposity and insufficient physical activity are prevalent in older adults and independently contribute to the age-related decline in GH and IGF-I secretion (1,4). Notably, elevated adiposity further reduces serum IGF-I concentrations independent of chronological age.

Several mechanisms could explain the relationship between BMI and GH. Some studies have shown that increased abdominal visceral fat mass is the best predictor of GH secretion attenuation in humans, and that dietary restriction leading to substantial weight loss restores GH secretion. The pathophysiological pathways involved in GH suppression in obesity are not well established, and experimental data on central effects via hypothalamic GHRH, ghrelin, and somatostatin are conflicting (20). Several feedback mechanisms have been proposed, including via insulin, free IGF-I, and free fatty acids (FFA). Acute elevation of FFA in normal subjects diminishes GH secretion, while lowering of FFA in obese subjects increases spontaneous GH secretion, possibly by a direct effect on the somatotrophs. Since both aging and obesity are linked to elevated plasma insulin levels, a potential mechanism underlying these effects may involve increased insulin activity on hypothalamic and/or pituitary IGF-I receptors. This could lead to enhanced feedback inhibition of growth hormone (GH) secretion and, consequently, reduced IGF-I secretion (21).

In a retrospective study wherein BMI was used as a proxy for adiposity (median age 40 yr, range 20–77 yr, median BMI 26 kg/m2, range 18.3–49.8 kg/m2), total and pulsatile 24 hour GH secretion were both negatively associated with BMI, and GH secretion was higher in women than men below 50 years of age, likely due to the influence of estradiol levels on IGF-1 levels (22) (Figures 3,4).

FIGURE 3.

Total 24-hour GH secretion in 130 healthy adults plotted versus BMI and age. Blue symbols reflect the data points above the regression plane, while the green circles represent data under the regression surface. From Roelfsema F, Veldhuis JD. Neuroendocrinology, 2016, Vol 103, 335–344.

FIGURE 4.

Pulsatile 24-hour GH secretion in 130 healthy adults plotted versus BMI and age. Blue symbols reflect the data points above the regression plane, while the green circles represent data under the regression surface. From Roelfsema F, Veldhuis JD. Neuroendocrinology, 2016, Vol 103, 335–344.

GH and IGF-I secretion are modulated by sex steroids at different stages of life. Pubertal increments in estradiol (E2) and testosterone (T) increase GH pulsatility. In adulthood, a direct relationship exists between serum E2 and GH secretion, which is stronger in women than in men. With advancing age, GH secretion declines in postmenopausal women, whereas a decline in serum T is directly associated with decreases in indices of GH secretion in older men (22).

GH AND CARDIOVASCULAR CHANGES

Extensive research has shown that adult GH deficiency (AGHD) is associated with low-grade inflammation, oxidative damage, a prothrombotic tendency, an impaired adipokine profile, subclinical left ventricular (LV) dysfunction, and metabolic syndrome (23). The most important physiological effects of the GH/IGF-I axis on the cardiovascular system (CVS) and the effects of GHD on the CVS are summarized below (Figure 5)

FIGURE 5.

Overview of the cardiovascular effects of the GH/IGF-1 axis. (GH: Growth Hormone, IGF-1: Insulin-like Growth Factor 1, NO: Nitric Oxide, SMC: Smooth Muscle Cell).

DECREASED GH IN NORMAL AGING: SIMILARITIES WITH AND DIFFERENCES FROM ADULT GROWTH HORMONE DEFICIENCY

While not identical to aging, adult growth hormone deficiency (AGHD) provides the most comprehensive data on reduced GH secretion, treatment effects, adult dosing strategies, and the safety and side effects of GH replacement.

Normal aging shares several features with AGHD syndrome, including reduced muscle and bone mass, increased visceral fat, reduced exercise and cardiac capacity, atherogenic lipid profile changes, thinning skin, and various psychological and cognitive issues (24-25) (Table 1). While these changes in age-related GH deficiency are less severe than in AGHD, they are still clinically important (26)

It is important to distinguish the normal physiological decrease in GH secretion associated with aging from true pathological AGHD. Although aging is a state of relative physiological GH deficiency, it is not a disease in itself and is clearly distinct from AGHD. This is demonstrated by higher GH secretion and physiological responses seen in older adults when compared with AGHD patients of similar age (25). Moreover, aging per se is not an indication for AGHD diagnostic testing or GH administration.

Biochemical tests for AGHD diagnosis are imperfect, and their accuracy is strongly affected by the pre-test probability of the condition. Therefore, the most important indicator of GHD likelihood is the clinical context (26).. Most cases result from tumors within the sella turcica or their treatment, such as surgery and radiation, though other causes exist. Traumatic brain injury is an increasingly recognized cause of AGHD and may occur without coexisting deficiencies in other anterior pituitary hormones (27). Serum IGF-I levels alone are usually insufficient for diagnosing AGHD, so provocative tests such as the insulin tolerance test, glucagon stimulation test, or the combined GHRH-arginine test (where available) are needed (28).

The GHS and ghrelin mimetic, macimorelin, has recently been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the diagnosis of AGHD and is also available in Israel, South Korea, and the United Kingdom. Macimorelin provides a simple, orally available, well-tolerated, reproducible, and safe diagnostic test for AGHD, with accuracy comparable to that of the insulin tolerance test in adults (29). Because studies of macimorelin excluded individuals aged 65 or older or with a BMI >40, the safety and efficacy of this test in these populations have not been established.

CLINICAL CONSEQUENCES OF AGE-RELATED DECREASE IN GH SECRETION

Aging and GH deficiency both lead to reduced protein synthesis, loss of lean and bone mass, and increased body fat. With age, caloric intake and energy expenditure drop, while older adults typically weigh about 25% more than younger adults (23,24). Protein synthesis declines with age, and men lose roughly 12 kg (27%) and women 5 kg (15%) of lean body mass from ages 25 to 70, as measured by potassium-40 counting. Body fat rises by about 18% in men and 12% in women between the ages of 18 and 85. Reduced physical activity and higher carbohydrate intake may contribute to increased body fat, but they do not fully account for the up to 50% decrease in lean body mass observed between ages 20 and 80.

Age-related changes in organ structure and function observed in older adults resemble those seen in patients with pathological GH deficiency. Reduced activity of the GH/IGF-I axis in aging suggests this decline may contribute to altered body composition, sarcopenia, and frailty among the elderly.

The decline in GH may also contribute to the cognitive changes observed with aging. One of the many systems for classifying cognitive domains groups them into “crystallized” and “fluid” intelligence. Crystallized intelligence generally refers to vocabulary and long-term memory, whereas fluid intelligence includes short-term memory and active problem-solving and demonstrates a more marked age-related decline. Several studies have shown a correlation between serum IGF-I concentrations and performance on tests of fluid intelligence (30), suggesting that GH may play a role in maintaining fluid intelligence.

Mechanistic insights into the role of GH and IGF-I secretion in age-related alterations in cognitive function were assessed in several preclinical studies by Sonntag and colleagues, demonstrating somatotropic effects on rodent brain aging (31). These studies suggest that deficiencies in GH and IGF-I contribute to a functional decline in senescent rats, whereas augmentation of GH or IGF-I improves cognitive function, increases glucose utilization throughout the brain, increases cortical vascularity, and ameliorates age-related decline in hippocampal neurogenesis. Although some small clinical studies suggest a positive effect of GHRH or GH replacement on cognition (32), there are insufficient data to recommend testing GH deficiency or GH administration solely for this purpose.

GROWTH HORMONE IN AGING: CAVEATS REGARDING LONGEVITY

Animal research has questioned the hypothesis that interventions aimed at increasing GH secretion and IGF-I are truly beneficial (33). In numerous species, from nematodes to rodents, caloric restriction, which lowers IGF-I levels, has been associated with increased lifespan.

Mice with GH resistance and profoundly reduced IGF-I levels appear to be healthy and to exhibit increased life expectancy, along with reduced fasting glucose and circulating insulin concentrations (34). In mice carrying mutations in the gene required for pituitary cells to produce GH, lifespan is extended by 42% and tumor development occurs later (35). The effects become more pronounced when combined with caloric restriction, whereas GH administration shortens lifespan.

Mice treated with a metalloproteinase that cleaves an IGF-binding protein and decreases IGF-I bioavailability have a 38% longer lifespan and a lower tumor incidence. In experiments conducted with a mouse strain prone to age-related cognitive decline and decreased life expectancy, treatment with a GHRH-receptor antagonist increased telomerase activity, improved some markers of oxidative stress and cognition, and increased mean life expectancy (36). In contrast, mice treated with a GH antagonist made by replacing a single amino acid in the GH chain did not show an increased lifespan.

Thus, experimental studies have shown that mice lacking GH secretion or GH receptors live longer than wild-type mice, contradicting the idea of GH as an “anti-aging” hormone and supporting the concept of growth acceleration as a determinant of life potential.

The mechanisms underlying enhanced longevity in these mouse populations are multiple and complex. Some mouse models with extended lifespans exhibit insulin resistance; however, those that progress to overt diabetes experience a shortened lifespan. Long-lived mice are either leaner than normal or have increased subcutaneous adipose tissue, both of which may exert protective anti-aging effects. Caloric restriction and reduced GH/IGF-I signaling improve resistance to cellular stress and inhibit mTOR, thereby increasing longevity and possibly enhancing tumor resistance.

The relevance of these pre-clinical data to human aging remains uncertain. The latter concept is underscored by reports showing that longevity decreased rather than increased in a Brazilian population of women harboring a GHRH receptor mutation (37) and in a Swiss cohort of patients with isolated GH deficiency due to a homozygous mutation spanning the GH1 gene (38). In comparison, in an Ecuadorian kindred with GH receptor deficiency and very low levels of IGF-I, rates of cancer and diabetes were markedly reduced compared to unaffected people in the same communities (39). A group of Croatian patients with dwarfism and multiple hormone deficiencies (GH, TSH, PRL, FSH/LH) related to homozygous PROP1 mutations do not experience diabetes mellitus, early grey hair, or death (40). Ultimately, although size and lifespan appear to exhibit an inverse relationship in some animal studies, no such formal longevity studies have been performed in humans with dwarfism or short stature.

CARDIAC EVALUATION AND MONITORING

Adults with GHD have an increased risk of cardiovascular morbidity and mortality; therefore, it is essential for these patients to undergo regular evaluation of cardiovascular parameters. Recent guidelines from the AACE and ACE recommend monitoring blood pressure and heart rate every 6–12 months. Further evaluation, including electrocardiography, echocardiography, and carotid echo-Doppler examination, can be performed if clinically indicated (23).

Echocardiography is commonly used to assess cardiovascular health in AGHD patients and can reveal reduced LV mass and function. GH replacement therapy (GHRT) improves these parameters (23). The American Society of Echocardiography recommends 2D echocardiography for monitoring LV mass index (LVMI) and ejection fraction (EF). New techniques such as 3D and speckle-tracking echocardiography (STE) provide further insights into heart function, showing that Global Longitudinal Strain (GLS) may be a better prognostic indicator than EF (41). Cardiac Magnetic Resonance Imaging (CMRI) is a highly accurate method for evaluating cardiac function and morphology in AGHD patients and can confirm increased LVMI in response to GHRT. Gadolinium enhancement indicates myocardial viability and is useful in patients with ischemic heart disease (41, 42). Carotid ultrasound measures carotid plaque burden and intima-media thickness (CIMT), both of which are critical for cardiovascular risk assessment. Increased CIMT is linked to atherosclerosis and may improve with hormonal therapy in AGHD patients (43).

AVAILABLE GROWTH HORMONE STIMULATION TESTS

GROWTH HORMONE THERAPY IN NORMAL AGING

A large body of literature of over 2000 published papers has led to a consensus that GH replacement can reverse many abnormalities in AGHD patients. Reviews of the topic report beneficial outcomes such as reduced fat mass, increased lean body mass, improved exercise capacity and cardiac function, increased bone mineral density, and enhanced quality of life, as measured by subjective and objective measures (50-52).

The similarities between aging and adult GH deficiency, while not exact, have stimulated interest in administering GH directly or stimulating GH secretion in older adults. However, the starting point and the target are not the same in the two conditions, and we cannot assume safety and efficacy will be the same.

To date, studies of interventions to increase the effects of GH in elderly subjects include administration of GH, IGF-I, GHRH, and a ghrelin mimetic (GHS), either alone or in combination with sex steroids or exercise. The first studies of GH treatment in non-GHD older adults were performed not long after its effects in AGHD were demonstrated. In 1990, Rudman and colleagues reported that healthy men above the age of 60, who were treated with GH for 6 months, responded with an 8.8% increase in lean body mass, a 14.4% decrease in adipose tissue mass, and a 1.6% increase in bone mineral density (BMD) only at the vertebral spine (53). Although the change in BMD was quite small, it was especially remarkable given that most studies of AGHD have required 1 year or more of therapy to show improvement in bone density. Those changes in body composition persisted after one year of growth hormone treatment (54).

Although the Rudman study did not assess functional measures, researchers suggested that GH treatment might also enhance muscle strength and functional performance. Attempts to replicate the higher GH doses used in the study by Rudman et al. in older adults resulted in a high incidence of adverse effects, including fluid retention, joint pain, muscle pain, carpal tunnel syndrome, and impaired glucose tolerance (59). Consequently, subsequent studies and clinical guidelines have emphasized the importance of using lower GH doses in elderly individuals aged 60 years or older to reduce side effects. The American Association of Clinical Endocrinology and the Endocrine Society both assert that GH therapy should only be used in adults who have confirmed GHD. It should not be administered for age-related declines in GH or IGF-I levels in otherwise healthy elderly individuals. The goal is to adjust doses to maintain IGF-I levels within the age-appropriate normal range, rather than achieving the levels typically seen in younger adults (44).

GH THERAPY GUIDELINES FOR THE ELDERLY

EFFECTS OF GH THERAPY ON METABOLIC SYNDROME AND CARDIOVASCULAR RISK FACTORS

In a single-center observational study by Scarano et al., the authors evaluated the long-term effects of growth hormone (GH) therapy over an approximate 7-year follow-up period. The study observed that prolonged recombinant human GH (rhGH) treatment in patients with growth hormone deficiency (GHD) was associated with improvements in body composition and lipid profile. Specifically, patients receiving GH therapy exhibited lower LDL-C and triglyceride levels, higher HDL levels, and reduced waist-to-hip ratios compared with controls. These beneficial effects were more pronounced in younger adults than in elderly GHD patients. No significant differences were observed between adult and elderly cohorts regarding blood pressure, hemoglobin A1c, and the prevalence of metabolic syndrome, as assessed by IDF and ATPIII criteria (56)

EFFECTS OF GH THERAPY ON PHYSICAL STRENGTH AND PERFORMANCE

Interest began with the above-mentioned study (53) and subsequent short-duration studies, which showed that GH administration to healthy older adults, to equalize serum IGF-1 with that of young people, increased lean mass and reduced body fat mass. However, studies largely found inconsistent and unimpressive results for physical function, particularly muscle strength and maximum VO2 capacity.

In a large study comparing 6 months of growth hormone treatment with placebo in men aged 70 to 85, Papadakis and colleagues reported a 13% reduction in fat mass and a 4% increase in lean body mass in the treatment group. Effects were consistent with earlier studies; however, no impact of GH was found on knee extension, handgrip strength, or endurance (57). It should be noted that these unfavorable outcomes may be influenced by the high baseline functional status of the study participants, as many were already performing near the upper limits on several assessments prior to treatment.

In a separate study, Taaffe and co-workers showed that exercise training improved strength and exercise capacity but added GH treatment did not further augment this effect (58). Since then, several similar studies have been carried out. Each of these studies was conducted at a single site for 6-12 months; therefore, only short-term outcomes and side effects, but not long-term risks, could be observed (59). Thus, the results of those studies do not provide guidance on the effects of GH therapy on long-term clinical outcomes, endpoints such as falls or fractures, maintenance of functional status, or cardiovascular morbidity and mortality – outcomes that could more definitively establish the rationale for GH treatment in normal aging. Though a few long-term risks have been observed, this is mainly indicative of an absence of information rather than a demonstration of safety. In 2004, a review of various interventions for sarcopenia and muscle weakness in the elderly concluded that GH therapy was associated with a high incidence of side effects and did not increase strength. Furthermore, resistance training is the most effective intervention for increasing muscle mass and strength in the elderly (60).

In 2007, Liu and colleagues published a systematic review of the safety and efficacy of GH administration in the healthy elderly (59). They reported that, after a mean treatment duration of 27 weeks, GH-treated individuals exhibited a decrease in fat mass of 2.1 kg and an equal increase in lean body mass of 2.1 kg, with no change in overall weight. Total cholesterol levels trended downward by 11.2 mg/dL, though not significantly, after adjustment for changes in body composition. Outcomes, such as bone density and other serum lipid concentrations, did not change significantly. Although women received higher doses of GH relative to their body weight, they did not experience an increase in lean body mass and showed only marginally significant reductions in fat mass, indicating a difference in response to GH therapy between males and females. Individuals treated with GH experienced a significantly higher frequency of soft tissue edema, arthralgias, carpal tunnel syndrome, gynecomastia, impaired fasting glucose, and diabetes mellitus onset.

EFFECTS OF GH THERAPY ON COGNITION, SLEEP, AND MOOD

As noted above, rodent studies have shown that GH administration increases brain vascularity and improves performance on some cognitive tests, but systematic evaluations of the cognitive effects of GH administration in humans are lacking (61). A seemingly contradictory finding was reported in 2017 by Basu and colleagues, who demonstrated that spatial learning and memory were improved in 12-month-old GH receptor antagonist transgenic mice when compared to their wild-type controls. They proposed that GH antagonism may also have cognitive benefits in aging rodents (62). However, a trial of GH therapy in patients with Down Syndrome showed an increase in head circumference but no effect on cognitive performance (63). Early reports suggested that GH boosted slow (deep) wave sleep (SWS), but subsequent studies have failed to confirm this and instead have reported more sleep fragmentation and decreased total SWS (32). While GH treatment in adults with GH deficiency improves self-reported quality of life scores on various questionnaires, there is still little solid, comparable data available for its effects on normal aging.

EFFECTS OF GH THERAPY IN COMBINATION WITH SEX STEROIDS

In a 6-month study of healthy men and women over the age of 65 treated with GH alone or in combination with estrogen/progestin in women and testosterone in men, lean body mass (LBM) and % total body fat were assessed by dual X-ray absorption (DEXA), before and after 6 months of the hormonal administration (64) (Figures 6-8). The three active treatment arms, testosterone (T), GH, and GH+T, tended to increase LBM significantly compared to the placebo group and within the groups compared to their own pre-treatment values. GH increased LBM by 5-6% in those men. Testosterone increased LBM by 3-4%. Combined administration of GH+T elicited an additive effect, increasing LBM by 8.5%. Muscle strength increased marginally, and VO2 max augmented significantly in men, only in the GH+T group. In women, GH, but not estrogen + progestin, increased LBM and decreased fat mass, with no effects on muscle strength or VO2max. Adverse effects were frequent, especially glucose intolerance, which was reversible after stopping hormone intervention. There was no evidence that sex steroids co-administration altered the frequency or severity of GH-related side effects.

Figure 6.

Effects of Hormone Administration on Lean Body Mass (DEXA) in Healthy Elderly Women and Men. From Blackman MR et al, JAMA, 2002.

Figure 7.

Effects of Hormone Administration on Total Body Strength in Healthy Elderly Women and Men. From Blackman MR et al, JAMA 288: 2282, 2002.

Figure 8.

Effects of Hormones on Maximum Aerobic Capacity (ml O2/min/kg BW) in Healthy Elderly Women and Men. From Blackman MR et al, JAMA 288: 2282, 2002.

A 2006 British study randomized healthy older men to 6 months of treatment with GH, a T patch (T), or a combination of GH and T (GH+T), and compared their results with those of a placebo group (65). GH-treated groups experienced comparable increases in lean body mass, whereas this measure was unchanged by T treatment alone. Fat mass decreased only in the GH+T combination group. Similarly, mid-thigh muscle cross-sectional area and exercise capacity (VO2 max) increased only in the GH+T group and not in the GH or T only groups. There was no difference among the groups in 5 of 6 muscle strength measures, except for knee flexion strength, which was increased in the GH+T group. GH-treated groups reported improvement in a QoL questionnaire. Overall, GH treatment was well tolerated in this study, and most side effects resolved with simple dose adjustments.

In 2009, another study explored whether supplementing older men with both T and GH could improve body composition and muscle performance (66). A total of 122 community-dwelling men, averaging 70.8 ± 4.2 years old, with a BMI of 27.4 ± 3.4 kg/m², T levels of 550 ng/dl or less, and IGF-I in the lower adult tertile (≤167 ng/dl), were randomly assigned to receive transdermal T (5 or 10 g/day) during a Leydig cell clamp, along with GH (0, 3, or 5 μg/kg per day) for 16 weeks. Supplemental T led to notable increases in total and appendicular lean mass, muscle strength, and aerobic endurance, along with marked reductions in whole-body and trunk fat. These results seemed even better when combined with GH supplementation to receive transdermal testosterone (5 or 10 g/day) during a Leydig cell clamp, along with GH (0, 3, or 5 μg/kg per day) for 16 weeks (66).

EFFECTS OF GH THERAPY AND EXERCISE

Regular exercise has been shown to increase lean body mass, muscle strength, and aerobic capacity in older men (67). Vigorous exercise acutely stimulates GH secretion, a physiologic response that has been utilized as a screening test for GH deficiency in children.

The fact that the acute GH response to exercise decreases with aging has led to speculation that some of the effects of exercise might be mediated by GH and IGF-I. Despite the effects of exercise to induce an acute rise in GH secretion, subsequent overnight GH secretion is impaired (68). In older adults, even intensive exercise does not elevate serum IGF-I level (69). These observations suggest that the benefits of exercise on muscle mass and function are likely independent of GH actions.

Studies assessing the effects of adding GH to progressive resistance training regimens in older adults have found little to no additional benefit of GH therapy on muscle strength or other measures of muscle composition but did find that GH therapy led to greater reductions in fat mass than resistance training alone (57, 70).

EFFECTS OF GH THERAPY ON OBESITY RELATED MASLD

GH activates intracellular signal transduction pathways via its type I cytokine receptor, GHR. The best-understood action is GH/GHR-mediated phosphorylation of STAT5, which stimulates hepatic IGF-1 production and its binding proteins. Hepatic IGF1 accounts for most of the circulating IGF. Obesity is associated with decreased GH and IGF1, which are linked to the development and progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) (71). Although limited clinical trials exist, evidence suggests that low circulating GH and IGF1 contribute to the progression of these conditions. Enhancing the GH axis activity has been shown to reduce liver fat, inflammation, and fibrosis, potentially improving MASLD outcomes, especially in adults with prediabetes or well-controlled diabetes, where GH supplementation is well-tolerated with proper glycemic monitoring. Clinical and animal studies show that GH and IGF-1 improve whole-body nutrient utilization, reduce inflammation, and enhance insulin sensitivity, thereby helping shift nutrients away from the liver. These effects are most evident when GH levels are maintained in a physiological range. Additionally, preclinical models have highlighted liver-specific actions of GH and IGF1 that may prevent MASLD progression. Given the clinical burden of MASLD and the limited number of FDA-approved treatments, further research into the therapeutic potential of GH and/or IGF-I could lead to new targeted therapies (72).

In 2023, a randomized, double-blind, placebo-controlled trial evaluated the effects of low-dose GH on MASLD in otherwise healthy adults with MASD but no hypopituitarism. The cohort included 53 adults aged 18 to 65 years (mean age, 46 years), all with a BMI ≥25 kg/m2. The results showed that administering daily subcutaneous GH to subjects with overweight/obesity and MASLD led to a 9% absolute reduction in liver fat (intrahepatic lipids) compared with placebo, as measured by the gold-standard method of proton magnetic resonance spectroscopy (1H-MRS) (73). Beneficial changes persisted after adjusting for age, sex, and change in BMI, using a sensitivity analysis that excluded all subjects with ≥3% weight loss, which itself has been shown to result in significant improvements in hepatic steatosis.

In conclusion, low-dose GH administration to healthy adults with overweight/obesity and MASLD decreases liver fat and liver cell damage without causing adverse glycemic effects or increasing insulin resistance. To date, there has not been a similar study focused on elderly patients with overweight /obesity and MASLD; thus, further research is needed to determine the possible effects of GH in this specific population.

GH THERAPY AND POST MENOPAUSAL OSTEOPOROSIS

The GH/IGF-1 axis plays an important role in maintaining skeletal homeostasis by stimulating osteoblast differentiation and bone formation. In adults with pituitary disorders, GH deficiency is characterized by low serum levels of GH and IGF-1, which have been shown to cause low bone mineral density and a high risk of fractures.

In 2015, a study followed 80 women aged 50 to 70 with osteoporosis who were receiving estrogen hormone replacement, comparing them with 120 age-matched women from the general population (74). Participants were randomly assigned to receive daily subcutaneous injections of either 1.0 U or 2.5 U of recombinant human growth hormone (GH) or a placebo for 3 years. All also took 750 mg of calcium and 400 U of vitamin D and were monitored over a 10-year period. Bone mineral density (BMD) and content were measured using dual-energy X-ray absorptiometry, and quality of life (QoL) was assessed with the 36-item Short Form. GH increased BMD and bone mineral content in a dose-dependent way across all regions (P = 0.01 for 1.0 U, P = 0.0006 for 2.5 U vs placebo). After 10 years, fracture rates dropped from 56% to 28% (P = 0.0003) among patients, while in controls they rose from 8% to 32% (P = 0.0008). QoL remained unchanged during GH treatment and throughout follow-up, with no difference from controls. Overall, GH treatment improved bone health and reduced fractures but had no impact on QoL in women with postmenopausal osteoporosis. In contrast, a systematic review and meta-analysis of GH therapy and BMD in patients without AGHD showed no significant improvement in BMD at the lumbar spine, total hip, or femoral neck compared with the placebo group (75).

Larger, long-term studies are needed to confirm and extend these findings, and to investigate the effects of GH on bone quality, as well as its potential benefits in clinical practice.

ADVERSE EFFECTS OF GH THERAPY

Side effects observed in clinical trials of GH treatment for normal aging should be distinguished from those in patients receiving treatment for AGHD. The possibility that some of the hormonal changes observed with aging could represent adaptive responses must be considered. Whether increasing GH above the age-appropriate normal range may have as many risks as benefits, both acute and delayed, is an important hypothesis to examine. The most worrisome long-term potential side effect, of special importance in the older population where baseline risk is elevated, is the risk of cancer. Though there is no definitive evidence that GH replacement in AGHD increases the risk of de novo or recurrent malignancy, several case reports note the development of cancer after treatment with GH, and because it is a mitogen, the use of GH is contraindicated in patients with an active malignancy (50,51). Nevertheless, GH replacement is not associated with tumor regrowth in AGHD patients with pituitary tumors.

Older adults are more sensitive to GH replacement and more susceptible to suffering from adverse events (44). Acute side effects of GH are usually due to the hormonal effects of over-replacement, which can be avoided or relieved with careful dose titration. Patients who are older, heavier, or female are more prone to develop complications (27). Common side effects of GH replacement include fluid retention, peripheral edema, arthralgia, and carpal tunnel syndrome. Although serum glucose concentrations often increase after GH initiation, they generally return to normal as body composition improves and insulin resistance decreases. However, some studies report persistent elevations in fasting glucose and insulin with chronic GH treatment. Less frequently reported side effects include headache, tinnitus, and benign intracranial hypertension (27). Hypothyroidism is common in older adults, and GH can speed up the clearance of thyroxine while also promoting its conversion to triiodothyronine. As a result, it may have varying effects on hypothyroid patients who are receiving thyroid hormone replacement.

EFFECTS OF GROWTH HORMONE RELEASING HORMONE (GHRH) AND GROWTH HORMONE SECRETAGOGUES (GHS)

GHRH and GHS stimulate GH secretion. Since most AGHD is caused by pituitary lesions, and these patients, unlike healthy, older adults, are unresponsive to GHRH or GHS, there are few studies of treatment with these agents (4).

Treatment with GHRH or GHS results in more physiologic GH responses, with a pulsatile rather than prolonged GH elevation, and preserves the ability of negative feedback inhibition of GH by increasing IGF-I. GHRH and GHS effects are influenced by the same factors that modulate endogenous GHRH secretion, such as somatostatin-mediated negative feedback. This physiological negative feedback regulation would be expected to result in buffering against overdose. The side effects of GHRH treatment are similar in character to those of GH treatment but are milder and less frequent. Because GHS are smaller molecules than GH, and generally resistant to digestive enzymes, they can be administered by oral, transdermal, or nasal routes (76).

EFFECTS OF GROWTH HORMONE RELEASING HORMONE (GHRH)

Several published trials have examined GHRH treatment in older adults (76, 77). Once-daily GHRH injections elicit increases in GH and IGF-I, at least to levels in the lower range observed in young adults (76). In a study of 6 months of treatment with daily bedtime subcutaneous injections of GHRH (1–29) NH2 or Sermorelin, alone or in combination with formal exercise conditioning, IGF-I levels increased by 35% (76). Participants showed increases in lean body mass and decreases in body fat (primarily visceral abdominal fat); however, there were no improvements in strength or aerobic fitness. This study also found that IGF-1 levels did not significantly change during exercise. Thus, it appears that GH/GHRH and exercise work through different mechanisms. Subjects receiving GHRH also showed no change in their scores on an integrated physical functional performance test of activities of daily living, while the placebo group experienced a noticeable drop in physical function. These results suggest that GHRH can stabilize or improve physical function compared with placebo but require confirmation in further clinical trials.

Sleep and cognition were also studied in the GHRH trial which found that GHRH failed to improve and may even have impaired slow wave (deep) sleep, despite the rise in IGF-I and pulsatile GH. In comparison, GHRH treatment was associated with improved scores in several domains of fluid intelligence, but not crystallized intelligence, and these measures were directly related to circulating IGF-I levels (30).

A 2006 study of the effects of 6 months of daily administration of sermorelin acetate, a GHRH analogue, on cognitive function in 89 elderly adults found significant improvement on several cognitive assessments, particularly those involving problem solving, psychomotor processing speed, and working memory, but no change on tests reflecting crystallized intelligence (32). Higher GH levels were associated with higher Wechsler Adult Intelligence Scale performance IQ scores, and greater increases in IGF-1 were associated with higher verbal fluency test scores, while gender, estrogen status, and initial cognitive function did not influence the GHRH effect on cognition.

In 2013, a pilot study involving 30 elderly adults tested a stabilized analogue of GHRH, tesamorelin, against a placebo, using magnetic resonance spectroscopy to explore the effects on inhibitory and excitatory neurotransmitters (78). After 20 weeks of treatment, GABA levels increased in all brain regions, N-acetylaspartylglutamate levels rose in the dorsolateral frontal cortex, and myo-inositol (an osmolyte linked to Alzheimer’s disease) levels decreased in the posterior cingulate. Similar results were observed in adults with mild cognitive impairment (MCI) and in those with normal cognitive function. Changes in serum IGF-1 concentrations related to treatment were positively correlated with changes in GABA and negatively correlated with myo-inositol. Additionally, there was a favorable treatment effect on cognition (p=0.03), but there were no significant associations between treatment-related changes in neurochemical and cognitive outcomes.

A follow-up study involving 152 elderly patients receiving either tesamorelin or a placebo included participants with amnestic MCI and examined executive function, episodic memory, mood, sleep, insulin sensitivity, glucose tolerance, body composition, and IGF-1 levels (79). Tesamorelin improved cognition (p=0.002) in both groups. Serum IGF-I concentrations increased and were associated with greater composite changes in executive function scores (p=0.03). Visual memory, mood, sleep, hemoglobin A1c, 2-hour OGTT glucose, and insulin responses were not affected in either population, though tesamorelin treatment was associated with increased fasting plasma insulin concentrations in adults with MCI. Tesamorelin administration also reduced body fat by 7.4% (p<0.001) and increased lean muscle mass by 3.7% (p<0.001 in both study populations. Ultimately, the clinical significance of these results cannot be determined because no data was gathered on functional status.

In a 3-month, non-controlled trial of GHRH (1-44) amide involving 10 postmenopausal women, increases in both GH and IGF-I levels were observed, along with reductions in visceral fat (80). This study also reported improvements from baseline in selected measures of functional performance, such as timed walking and stair climbing.

Like GH, research on treating older adults with GHRH and its analogs agrees on its hormonal and body-composition benefits, but the functional outcomes remain mixed. There is a hopeful yet unproven improvement in some aspects of fluid intelligence.

GHRELIN MIMETICS

Ghrelin, a 28-amino-acid octanoylated peptide, is the endogenous ligand for the GH secretagogue receptor (GHSR)-1a. Ghrelin is produced in the stomach and increases before meals and during overnight fasting. Ghrelin acts at both the hypothalamic and pituitary levels via mechanisms different from those of GHRH. Ghrelin exerts effects distinct from those of GHRH or GH; subjects often gain body weight and lean and fat mass through a mix of GH-dependent and independent mechanisms (81). The effects of ghrelin on GH secretion partially depend on the presence of GHRH. If GHRH secretion declines with aging, as is thought to be the case, ghrelin’s effects may be blunted. GHRH and Ghrelin exert synergistic effects on GH release, and their combined administration may be more effective than that of either alone. Ghrelin is more potent than GHRH in stimulating GH secretion; additionally, other known substances that can enhance the GH response to GHS by suppressing somatostatin secretion, such as arginine and beta-adrenergic antagonists, can potentially boost the therapeutic effects of GH secretagogues.

Several studies have shown the short-term effects of GHS on GH secretion, but few have reported its chronic effects in older adults. Of note, Bowers and colleagues showed that chronic, repeated injections or subcutaneous infusions of GH-releasing peptide-2 (GHRP-2) could stimulate and maintain increases in episodic GH secretion and raise IGF-I levels (82).

Results of a one-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial of the orally active ghrelin mimetic MK-677 in healthy, high-functioning older adults were published in 2008 (83). Daily administration of MK-677 significantly increased GH and IGF-I levels to levels comparable to those of healthy young adults, without serious adverse effects. Mean fat-free mass decreased in the placebo group but increased in the MK-677 group. No significant differences were observed in abdominal visceral fat or total fat mass. Body weight increased 0.8 kg in the placebo group and 2.7 kg in the MK-677 group (p=0.003). Fasting blood glucose level increased an average of 0.3 mmol/L (5 mg/dL) in the MK-677 group (p=0.015), and insulin sensitivity decreased. The most frequent side effects were a transient increase in appetite that subsided in a few months, mild lower-extremity edema, and muscle pain. No differences between groups were observed in total or high-density lipoprotein cholesterol levels. Changes in bone mineral density consistent with increased bone remodeling occurred in MK-677 recipients. Increased fat-free mass did not result in changes in strength or function, as assessed by the 6-minute walk and stairs up/down tests.

A multicenter trial of another oral ghrelin mimetic, capromorelin, in pre-frail older men and women recruited more than 300 subjects and was initially planned as a two-year intervention. Capromorelin has appetite-stimulating effects that are primarily mediated through ghrelin-mimetic activity within the hypothalamus, where activation of neuropeptide Y and agouti-related peptide pathways enhances central hunger signaling (84). The study was stopped, however, after all subjects had been treated for 6 months and many for 12 months, due to failure to see an increase in percent lean body mass, which was a pre-set non-efficacy termination criterion. Absolute lean body mass did increase significantly, but due to the appetite-stimulating and lipogenic/anti-lipolytic effect of ghrelin mimetics – unforeseen in early 1999 when the study was designed, and ghrelin was still unknown – subjects also gained weight (about 1.5 Kg), and this washed out the effect on percent lean body mass. However, this study showed the expected increases in IGF-I levels and (as noted) total lean body mass. There were also encouraging effects on physical functional performance. Of seven functional tests, one improved significantly after 6 months of treatment, and another after 12 months. Two other measures showed non-significant trends toward improvement, and the three remaining measures showed no effect. Effects on clinical endpoints, such as falls, could not be assessed with this relatively brief treatment duration. Side effects were generally mild, including increases in fasting blood sugar within the normal range. Interestingly, self-reported deterioration in sleep quality was noted, although formal sleep testing was not performed. Cognition was not studied in this trial. The reasons for the differences in outcomes between the MK-677 study and this capromorelin trial are unclear. The results might reflect differences in the populations studied. The MK-677 study recruited a robustly healthy population of older adults in whom further improvement in physical function might be difficult to achieve, whereas the capromorelin trial was limited to participants already manifesting an early decline in function. Capromorelin is now FDA-approved as an appetite stimulant for dogs and cats.

Thus, as with GH and GHRH, reports on the hormonal and body-composition effects of ghrelin mimetics (GHS) in older adults are relatively consistent, but there is no consensus on functional effects among these few studies, and none have assessed long-term clinical outcomes or risks.

The novel ghrelin mimetic, anamorelin, is currently under clinical development for cancer anorexia and cachexia syndrome (CACS), a syndrome overrepresented in the elderly. In a phase II randomized, double-blind, placebo-controlled study, 3 days of treatment increased body weight and appetite in CACS patients when compared to placebo (85). Over 3 months of treatment, anamorelin increased body weight, LBM, hand grip strength, and quality of life (QOL). Anamorelin also increased IGF-1 and IGF-binding protein-3 (IGFBP-3). It was well tolerated but induced a small increase in glucose and insulin concentrations (86). Unfortunately, several large, international, randomized, double-blind, placebo-controlled phase III studies in patients with advanced non-small cell lung cancer and CACS (ROMANA and SCALA trials) did not show improvements in clinically meaningful outcomes of function (grip strength) or patient-reported outcomes [FAACT scale – Functional Assessment of Anorexia/Cachexia Therapy] with anamorelin, despite increased LBM, fat mass, and body weight compared to placebo (87). Although these studies were not restricted to the elderly, the mean age of the population was above 60 years in all studies.

CONCLUSIONS

Although normal aging is not a disease, it results in detrimental changes in body composition and functional decline, with subsequent frailty and loss of independence. Clearly, numerous gaps remain in clinical knowledge. Pharmacological and non-pharmacological Interventions that slow this decline can potentially prolong the capacity for independent living and improve quality of life, but this has not yet been demonstrated. It is unknown whether the age-related decrease in trophic hormones, including sex steroids and GH, represents an adaptive or pathological process, particularly when it is accompanied by the presence of symptoms and signs of hormonal deficits. Aging-related syndromes such as sarcopenia and/or frailty may represent opportunities to intervene with hormones, including GH, GHRH, or GHS. However, older persons may be more sensitive to these treatments and thus more susceptible to the adverse side effects. To date, definitive conclusions regarding the functional effects of treatments aimed at increasing GH levels in healthy aged individuals compared to those of young healthy persons have been elusive. Until more studies are undertaken to determine the long-term effects of GH and GHS supplementation, conclusive statements about the merits of treatment cannot be made. Long-term studies using hard clinical endpoints, such as falls and fracture rates, functional measures, quality of life, and morbidity and mortality from vascular disease, are needed to establish the potential role, if any, of GH and GHS treatment in normal aging. In the meantime, GH use for anti-aging purposes is not warranted and is currently prohibited by US federal law (88, 89).

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*

deceased, contributed to the 1st edition

†

contributed to the 1st edition