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Age-Related Changes in Growth Hormone Secretion: Should the Somatopause Be Treated?

[Sem Reproductive Endo 17(4):311-326, 1999. © 1999 Thieme Medical Publishers, Inc.
From http://www.medscape.com/thieme/SRE/1999/v17.n04/sre1704.01.cumm/pnt-sre1704.01.cumm.html ]

Abstract

Introduction

Less clear are the functional consequences of the decline in GH secretion that occurs with aging or the relative benefits and risks of GH replacement in older adults who would not be considered GH deficient in the classical sense. Secretion of GH varies markedly across the life cycle, reaching a peak in adolescence and then declining with age in both men and women, in a pattern that implicates both the effects of gonadal steroid withdrawal and effects that are age related and independent of steroid hormone levels.^[2,3] The levels of GH and its downstream effector insulin-like growth factor-I (IGF-I) in old age overlap those of younger adults with classical GHD, and many age-associated changes resemble those of GHD. These include an increase in body fat, especially visceral and abdominal fat, reductions in muscle and bone mass, reduced cardiac output and aerobic capacity, and changes in circulating lipid profiles that are atherogenic in other contexts.^[4,5] These parallels have prompted speculation that GH might be used to reverse some age-related changes even in otherwise normal adults. Beginning with the studies of Rudman and colleagues,^[6] a few studies have examined the short-term effects of stimulating or replacing GH in normal aging, although the number of published trials is still very limited. Although there has been a proliferation of clinics organized specifically to offer GH and other "antiaging" hormone replacement to normal older adults with the means to pay for it, GH is still not approved for this use in any country, and the balance of risks and benefits remains largely uncertain.

This article reviews the current state of knowledge of the age- and menopause-related decline in GH secretion, which some have called the "somatopause" -- its underlying mechanisms, interactions of sex steroids with GH secretion and GH action, the model of adult GHD as a guide to what treatment effects and side effects might be expected, and the limited available information about the effects of GH stimulation or replacement in normal aging.

Mechanisms of Age-Related Changes in GH Secretion and Action

Regulation of GH Secretion

Figure 1. Proximal neuroendocrine mechanisms for regulation of growth hormone (GH) secretion. Converging neurotransmitter and neuromodulator pathways regulate the proximal pathways shown here to provide the pattern of spontaneous episodic GH secretion and its responses to internal and external factors such as stress, exercise, meals, and sleep. Although the liver is the major source of IGF-I in circulation, locally generated IGF-I in other target tissues is likely to be more important as a mediator of many GH actions.^[33] Abbreviations: GHRH, GH-releasing hormone; SRIF, somatostatin; IGF-I, insulin-like growth factor-I; GHS-e, endogenous natural ligand for the GHS/GHRP receptor; U-factor, hypothetical intermediary for certain GHRP actions. (Modified from Cummings and Merriam.)^[5]

Figure 2. Episodic GH secretion in younger and older women and men. In both sexes, the decline in GH primarily reflects a reduction in GH pulse amplitude. (From Ho et al.)²

This consensus model has been challenged by the discovery by Bowers and colleagues^[9] of enkephalin-derived GH secretagogues (GHSs) that stimulate GH secretion by a mechanism completely different from that of GHRH. Selective modifications of these low-molecular-weight peptides have led to the development of GH-releasing peptides (GHRPs) that have no residual opioid activity but are potent GHSs.^[9] The GHRPs do not bind to GHRH receptors. However, distinct GHS receptors that bind GHRPs with high affinity have been demonstrated in the hypothalamus and pituitary, cloned, and sequenced (for review see ref. 10). This strongly suggests the existence of an endogenous GHS (GHS-e) and an additional system for regulation of GH secretion, possibly involving the participation of further intermediate factors ("U-factors," Fig. 1). With the use of reporters linked to the GHS receptor, a natural ligand for this receptor, "ghrelin", has recently been identified in the stomach and brain.^[74] Although GHRH and GHSs can stimulate pituitary GH secretion independently, the two systems are closely linked. The full effect of GHSs in vivo appear to involve secondary release of endogenous GHRH and synergism with the direct pituitary effects of GHRH. There is therefore a potent synergistic effect when GHRH and GHSs are given simultaneously, and administration of GHRH antiserum or antagonists markedly blunts the effect of administered GHSs.^[11-13] Several nonpeptide GHSs have been developed and found to be active when orally administered to humans.

GH Deficiency and Normal Aging

Although the phenotype of normal aging generally resembles that of GHD, its severity and underlying causes are likely to differ. Estrogens are potent stimulators of GH secretion, and the perimenopausal decline in estrogen secretion is a major contributor to declining GH secretion in later life. But beyond this, there is an age-related, sex hormone-independent decline in GH secretion that gonadal steroid replacement therapy does not fully reverse. We will consider estrogen-related and
estrogen-independent changes in GH separately.

At least four possible mechanisms could subserve the estrogen-independent, age-associated decrease in GH secretion. These are loss of pituitary responsivity to secretagogues, increased sensitivity to IGF-I feedback inhibition, declining hypothalamic stimulation by GHRH and/or the endogenous GHS, and increased secretion of somatostatin.

Although both spontaneous and stimulated GH secretions are reduced with aging, the pituitary remains responsive to direct stimulation by secretagogues. When one removes some of the other influences that blunt GH responses, including an increase in somatostatin, GH responses to GHRH can remain vigorous. In a study of carefully screened healthy older normal-weight adults in the Baltimore Longitudinal Study on Aging, Pavlov and colleagues^[15] found that the acute GH response to GHRH was well maintained even in old age (Fig. 3). Other studies with less restrictive exclusion criteria reported a decreased GH response in older subjects, but these findings could also be explained by factors such as obesity and increased somatostatin tone (see later), and loss of somatotroph responsivity is unlikely to be primarily responsible for the age-related decline in GH secretion.

Figure 3. GH responses (± SEM) to the intravenous injection of a single bolus of GHRH(1-44)NH₂, 1 mg/kg IV, in groups of healthy adults in three age ranges. (From Pavlov et al.)^[15]

Chapman and colleagues^[16] examined the effects of graded infusions of IGF-I on GH secretion in normal younger and older subjects and found no shift in the dose-response curve for IGF-I negative feedback with age. Thus, altered pituitary sensitivity to IGF-I is also not a likely explanation for declining GH secretion.

In studies showing reduced GH responses to GHRH or to GHSs with aging, coadministration of factors that are believed to suppress somatostatin secretion, such as arginine, can restore the GH responses in older subjects to those of young adults.^[17,18] These results strongly suggest that aging is associated with an increase in somatostatin tone, perhaps in turn due to the age-associated increase in body fat. Obese patients secrete markedly reduced levels of GH and show increased GH after weight loss.^[19] Even within the normal range, there is a negative correlation of GH secretion with body-mass index.^[15] Because GHD can be a cause as well as a consequence of increased central adiposity, these changes may be self-reinforcing if the stimuli to GH secretion are also gradually reduced with age.

Besides the increases in somatostatin, reduced secretion of GHRH or endogenous GHS may be part of the aging process. This is difficult to demonstrate directly, but elevations in GH secretion and IGF-I with repeated doses of GHRH suggest a relative deficiency of endogenous GHRH secretion. Reduced GH responses to GHRPs that cannot be fully restored by somatostatin antagonism have led Bowers and colleagues to postulate an age-related decline in the hypothesized intermediate for GHRP action, the so-called U factor. Until the chemical nature of this substance or its receptors is defined, this necessarily remains speculative.

Thus, the weight of current evidence suggests that the sex steroid-independent decline in GH secretion with aging is multifactorial. It probably includes a decline in GHRH secretion and in most individuals an increase in SRIF and arises largely above the pituitary level.

Sex Steroid Effects on GH Secretion

It has long been known that sex steroids increase both spontaneous and stimulated GH secretion. Episodic GH secretion increases dramatically at puberty,^[3] and sex steroid priming is routinely employed to increase the GH responses to provocative testing in children. In addition to this well-known effect, sex steroid administration increases 24-hour spontaneous GH secretion both in prepubertal children^[20] and in men with hypogonadotropic hypogonadism, an effect largely manifested as increases in GH pulse amplitude.^[21] Dihydrotestosterone does not exert a similar effect, suggesting that the effect of testosterone on GH may be mediated by its aromatization to estradiol.^[22]

These changes occur in reverse with the decline in estradiol secretion across menopause and the more gradual decrease in testosterone secretion in men. Older men and women have marked reductions in 24-hour GH secretion, and again the change appears to be due largely to changes in GH pulse amplitude.^[23]

A few studies have examined changes in the GH-IGF-I axis across the reproductive years in normally cycling women in order to characterize age-related changes during a time of relatively constant ovarian steroid secretion, and the results are not in complete agreement. Wilshire and colleagues^[24] examined daytime episodic GH secretion in the early follicular phase of younger (ages 19-34) and older (ages 42-46) women and found a marked decrease in integrated GH secretion in the older women (171 ± 35 vs. 427 ± 130 µg/min/L) despite maintained or even higher estradiol levels. There was a trend toward reduced levels of IGF-I that did not reach statistical significance. A follow-up study also did not show a reduction in levels of IGF-I or IGF binding proteins 1 and 3.^[25] However, Klein and colleagues,^[26] in a slightly larger study of similar design, reported no difference in mean GH levels or GH pulse amplitude or frequency between younger and older cycling women studied in the early follicular and midluteal phases but did report significantly lower IGF-I levels in the older women. Reconciling these results awaits further studies.

Although there are some direct effects of estradiol on pituitary somatotroph responses, most central effects of sex steroids are exerted above this level. Acute GH responses to GHRH injections differ little between prepubertal children and adults^[14] or between adult men and women.^[27] However, it has been difficult to correlate steroid-mediated changes in GH secretion with changes in GHRH or somatostatin gene expression, levels or secretion in experimental animals. The available information on these postulated mechanisms has been summarized.^[28]

Sex Steroid Effects on GH Action

Some of this information has long been available. High doses of estrogens were used to treat acromegaly prior to the availability of other therapies; they reduced symptoms and signs of GH excess despite having little effect on GH secretion. Bellantoni and colleagues^[29] showed that oral estrogens reduced circulating levels of IGF-I in older women but transdermal estrogen replacement did not have this effect. These authors suggested that estrogens inhibited the generation of IGF-I and that oral estrogens particularly inhibited hepatic IGF-I production and thus circulating IGF-I levels. In normal women, this effect triggers a compensatory increase in GH secretion, and therefore normal women do not have lower levels of IGF-I than men. In states in which these compensatory mechanisms are impaired, however, estrogen can partially block GH effects.

The effect of estrogens on IGF-I generation is highlighted in studies of differences in the responses to GH of men and women with GHD. Drake et al^[30] used a titrated GH dosing regimen based on circulating IGF-I levels and found that women required approximately 50% higher GH doses than men to achieve similar responses. A subsequent report indicates that women taking oral estrogens may need even higher relative doses -- twice those of men or of nonestrogenized women (899 ± 56 vs. 464 ± 65 µg/day for estrogenized vs. nonestrogenized women and 396 ± 15 µg/day for men).^[31]

Burman and colleagues^[32] gave similar doses of GH (per unit body surface area) to 21 GH-deficient men and 15 women over 9 months and found that the men had greater increases in IGF-I and greater effects on lipids, bone markers, and body fat. This suggests that the GH resistance may not be solely a hepatic effect and that estrogens may modulate GH responses in a variety of target tissues. This is potentially of much greater physiological importance. Although the liver is the major source of circulating IGF-I, which in turn is a major regulator of GH secretion, IGF-I is also generated locally in many GH target tissues, and these paracrine effects may be of greater importance to the physiological responses to GH than are the endocrine effects of circulating IGF-I. Yakar and colleagues^[33] showed that mice with selective deletions of hepatic IGF-I gene expression grew normally despite extremely low levels of circulating IGF-I.

In acromegaly and GHD, feedback modulation of GH secretion is lacking, and thus the GH resistance induced by estrogens would be expected to reduce IGF-I. The absence of a systematic reduction of IGF-I levels in normal women suggests that when this feedback is fully functional it can compensate for GH resistance by increasing GH secretion. However, the report of Bellantoni et al^[29] that oral estrogens reduce IGF-I levels in older women suggests that in aging this compensation may be incomplete. Even stimulation of GH secretion with an administered GH secretagogue may not restore these compensatory mechanisms in older adults. Khorram, et al^[34] reported that estrogen-replaced older women treated with a GHRH analogue for 20 weeks had reduced responses of IGF-I, skin thickness, and other anabolic markers and self-reported quality of life compared with men, despite GH responses that were at least as brisk. We and colleagues^[35] reported that there were significant differences in the GH and IGF-I responses to 6 months of treatment with GHRH in healthy older women receiving oral estrogen replacement compared with men and nonestrogenized women. Despite a twofold greater increment in GH secretion, the estrogen-replaced women had markedly reduced IGF-I responses, averaging less than 10%, compared with a 50% rise in IGF-I levels in men. This area is still incompletely delineated, but these results suggest that postmenopausal oral estrogen replacement may induce a state of relative functional GH resistance that is not fully reflected by circulating GH levels. One center for the treatment of adult GHD has found that switching estrogen-replaced, GH-deficient women from oral to transdermal estrogen cut the requirement for GH replacement in half.^[31] If replacing or stimulating GH in normal aging ultimately proves to be beneficial, the use of transdermal estrogens may be one way to maximize the effectiveness of this treatment.

Consequences of Reduced GH Secretion: The Model of Adult GHD

Adult GH Deficiency Syndrome

Most visible among these abnormalities are undesirable perturbations of body composition. There is a 7-10% increase in fat mass, distributed preferentially in the abdominal visceral compartment. When seen in other contexts, this "android" pattern of fat accumulation is associated with increased risk of cardiovascular disease, diabetes, and hypertension. Adults with GHD have a reciprocal 7-10% decrease in lean body mass (LBM). Some of this loss probably arises from diminished total body sodium and water, as GH is an antinatriuretic agent. However, numerous in vitro studies demonstrate that GH has direct anabolic effects on muscle. Moreover, skeletal muscle volume decreases in adults with GHD out of proportion to the loss of overall LBM (by up to 15%), and muscle strength is impaired. These findings suggest that adults with GHD undergo genuine muscular atrophy.

Adults with GHD lose cardiac muscle as well as skeletal muscle. Left ventricular (LV) wall thickness is markedly reduced and cardiac capacity consequently impaired, as evidenced by defects in LV ejection fraction, stroke volume, and cardiac index. In addition, GHD is associated with atherogenic lipid perturbations including increases in total cholesterol (by 20%), low-density lipoprotein-cholesterol (LDL-C) (34%), and triglycerides (76%), as well as decreased high-density lipoprotein-cholesterol (HDL-C) (34%). Furthermore, thrombogenic proteins such as fibrinogen and plasminogen activator inhibitor-1 (PAI-1) are increased, and hypertension may be more common. These anomalies conspire to cause premature atherosclerosis. Compared with normal subjects, hypopituitary patients have a 2-fold increase in cardiovascular mortality, a 3.4-fold increase in cerebrovascular mortality, and reduced overall life expectancy.^[42,43] Because other pituitary hormones besides GH are replaced in these individuals, GH deficiency has been blamed for the premature deaths. However, it is also possible that factors related to treatment of pituitary diseases, such as radiotherapy, could contribute to such statistics, especially those regarding cerebrovascular disease.

Exercise capacity is dramatically impaired in adults with GHD. Maximal oxygen consumption (VO₂max), a measure of overall aerobic fitness, is reduced by 20-30%. There are several apparent mechanisms to explain this, including the 10-15% loss of skeletal muscle strength, reduced cardiac capacity, and diminished red blood cell volume.

Through several diverse mechanisms GH exerts anabolic effects on bone, as it does with muscle; these actions continue throughout life, even after linear bone growth has ceased. GH stimulates both bone formation and resorption, leading to an overall increase in bone mineral density (BMD). Accordingly, in adults with GHD, BMD is reduced at several sites by at least one standard deviation compared with that in age-matched controls. This leads to an increased incidence of osteoporotic fractures.

The skin of adults with GHD is thin, dry, and cool, rendering venous access difficult. These changes probably arise because of the loss of a direct anabolic influence of GH on skin cells, exacerbated by reduced cardiac output. In addition, GH regulates eccrine sweat glands, and sweating is impaired in GHD, very likely contributing to poor exercise capacity.

Patients with GHD suffer numerous social and psychological disturbances (listed in Table 1) that generally involve low self-esteem and diminished energy and vitality. In addition to reporting such complaints on a variety of validated questionnaires, patients score poorly in more objective life tests such as marriage performance and socioeconomic status. Control populations used in the studies that have elucidated these findings are generally matched with regard to age, gender, height, and socioeconomic level. Nevertheless, it is difficult to rule out the possibility that low self-esteem could be contributed to by body image issues related to the shift from lean to fat mass and possibly to short stature if GHD develops before puberty.

Benefits of GH Treatment in GHD Adults

The impact of GH treatment on body composition in adult GHD is unequivocal: fat mass and volume are decreased (by 7-15%), with the greatest reductions seen in abdominal visceral depots; LBM and skeletal muscle volume are increased (by 5-10%). Most studies showed little change in overall body weight, but rather a shift from fat to lean mass. Although the increase in LBM can be partially accounted for by GH-induced water retention, observed elevations in total-body K⁺ demonstrate that GH also promotes genuine muscle growth. These favorable body composition changes are more pronounced in men than women and more in young patients with low GH binding protein levels.

Another universal finding is that GH replacement improves cardiac performance. Investigators report increases in LV ejection fraction, stroke volume, and cardiac output, as well as decreased peripheral vascular resistance. These desirable changes are sustained for at least 3 years of therapy and may arise at least in part from preload augmentation resulting from GH-mediated increases in intravascular volume. It is controversial whether there is a small increase in LV muscle mass as well. Exercise performance also undoubtedly improves. VO₂max, a barometer of aerobic capacity, is nearly normalized with treatment. Muscle volume rapidly increases, in part due to GH-mediated water retention. Actual muscle strength also improves but only after 6 to 12 months of therapy, depending on the muscle site, and continues to increase for up to 3 years of therapy. Improvements in exercise performance are probably due to a combination of increased skeletal muscle strength, fat-to-lean alterations in body composition, expanded red blood cell volume (resulting from IGF-I stimulation of erythropoiesis), and enhanced sweating capacity.

GH replacement stimulates bone turnover and remodeling, as judged by increases in markers of both bone formation and resorption. Initially, the effects on bone resorption predominate, and BMD may fall slightly. However, after a year the reverse occurs, and BMD increases by 4-10%, a favorable change that is sustained for at least 2 years. These effects are maximal in patients with low initial BMD and least impressive in the elderly, in whom unrelated causes of osteopenia may be at work. The GH-induced increase in bone mass is fastest in trabecular bone and is thus manifest in vertebrae before the appendicular (cortical) skeleton.

The impact of GH replacement on serum lipids is less clear cut. GH regulates hepatic lipoprotein metabolism in a complex fashion, and GHD is associated with an atherogenic lipid profile. Replacement therapy modestly lowers total cholesterol, LDL-C, and apolipoprotein B and tends to lower triglycerides in patients with elevated baseline levels. There is also an equivocal elevation of HDL-C. These changes are all desirable with regard to cardiovascular risk, and they are maintained for at least 4 years with therapy. However, GH therapy also raises Lp(a), which is considered an independent risk factor for premature atherosclerosis and myocardial infarction. Considering the opposing effects of GH to lower LDL-C and raise lipoprotein (a) (Lp(a)), the overall impact of replacement therapy on the risk of cardiovascular disease is uncertain.

Although there are no published studies of the effects of GH replacement on the thin skin of adults with GHD, one study showed that GH treatment increased skin thickness among normal elderly men selected for low IGF-I levels.

GH therapy in adults with GHD rapidly increases resting energy expenditure by 12-18%, an effect that cannot be entirely accounted for by increased LBM. The known calorigenic actions of GH to increase of thyroxine conversion (T₄) to triiodothyronine (T₃) and to stimulate protein synthesis and fat oxidation presumably contribute to this increase in cellular metabolism.

Studies of the effect of GH replacement on psychological and social end points in adults with GHD have universally reported a therapeutic benefit. Improvements were found in subjective well-being, mood, energy, sleep, emotional reaction, behavior, pain perception, and overall quality of life. Observed changes were often subtle and/or erratic, and "blindedness" in these investigations is difficult to ensure because of GH-mediated symptoms such as fluid retention and arthralgias. Nevertheless, there is remarkable concordance among numerous trials using diverse questionnaires. The consensus is that through cryptic mechanisms GH treatment improves the overall well-being of adults with GHD.

In summary, GH replacement reverses most signs of GHD in young adults. Unfortunately, apart from favorable data on subjective quality of life, there is a paucity of information regarding the effect of GH replacement on clinically germane final end points as opposed to surrogate end points. For example, there are ample data on BMD but not on fractures, on muscle strength and exercise capacity but not functional status, and on body composition and lipids but not morbidity and mortality. The scarcity of subjects with GHD is a formidable obstacle to investigators wishing to undertake these important trials.

Adverse Effects and Potential Risks of GH Therapy

As GH directly antagonizes insulin action, a theoretical risk of its use is hyperglycemia. This is a particularly important concern for the elderly, as ~40% of people 65 to 74 years old and ~50% of those older than 80 years have impaired glucose tolerance or diabetes mellitus.^[45] Careful studies specifically examining this risk in GHD adults have shown that GH replacement does indeed initially decrease insulin sensitivity. However, the effect is reversed within 3-6 months of therapy, and carbohydrate metabolism returns to baseline. This is presumably due to the counteracting effect of losing central body fat and thus increasing insulin sensitivity. Although GH-induced increases in basal insulin or glucose have been seen in some studies, these values generally remained within normal ranges and were never associated with significant increases in hemoglobin A_1c.

Warnings have been voiced that GH could have mitogenic properties. These theoretical concerns derive from highly controversial in vitro data obtained with a variety of cell lineages, from the observation that most human solid tumors express IGF-I receptors,^[46] and from epidemiological evidence that patients with acromegaly have increased incidences of colon and breast cancer.^[47,48] However, it is inappropriate to extrapolate conclusions drawn from patients with acromegaly, who have grossly elevated GH levels, to adults with GHD receiving only physiological restitution. Furthermore, after more than 40 years of experience treating children with exogenous GH (at higher weight-adjusted doses than those used for adults), there is no convincing evidence of a GH-induced increase in cancer risk among these patients. It is true that this theoretical concern may be more germane to adults than children because of their higher baseline cancer risk -- especially in groups such as AIDS patients and the elderly, for whom GH therapy is being considered. Nevertheless, it is not presently recommended that individuals receiving GH therapy undergo any additional cancer surveillance beyond standard practices for prevention and early detection.

Reports of associations between circulating IGF-I concentrations and the development of prostate and breast cancer have further raised concerns about the long-term risks of GH therapy.^[49-51] However, IGF-I levels in the groups with increased cancer incidences were higher than those that would be sought in carefully titrated physiological replacement therapy. Thus, the applicability of these observations to the latter situation is questionable. Furthermore, there is no strong evidence for increased incidences of prostate or breast cancer in patients with acromegaly, which argues against a causal relationship between IGF-I and these malignancies. At present, the prudent course of action for patients receiving GH would be to adhere strictly to guidelines regarding prostate examinations and prostate-specific antigen (PSA) levels in men, and breast examinations and mammograms in women. Doctors should also inform high-risk patients of these reports.

GH administration is currently contraindicated for patients with active malignancy, benign intracranial hypertension, and proliferative or preproliferative diabetic retinopathy.^[52] Early pregnancy is not a contraindication, but GH therapy may be discontinued in the second trimester as a GH variant is secreted by the placenta.

One setting in which GH therapy has proved detrimental is in the critically ill. These individuals have impairments of both GH secretion and action. Hence, two randomized, multicenter trials were undertaken to determine whether GH treatment in several hundred intensive care unit patients might speed recovery.^[53] Unexpectedly, there was a near doubling of mortality, from 20 to 38%, in both studies. The authors speculate that increased calorigenesis, fluid retention, or immunomodulatory effects of GH may have contributed to the observed increase in mortality in the GH-treated group. Although similar adverse effects of GH treatment have not been seen in other settings, even at high doses in catabolic states such as burn states, the results suggest that part of the reduction in GH action in severe illness may be due to a physiologic adaptation. These effects are reminiscent of earlier reports that treating the "euthyroid sick syndrome" with exogenous T₃ can also have adverse effects. This prompts questions about whether reduced somatotropic activity might be adaptive in other conditions, such as aging.

Recommended GH Dosing

As described earlier, women are less sensitive than men to the effects of GH and thus require higher doses for equivalent results. This is especially true for women supplemented with oral estrogens, which may reduce hepatic sensitivity to GH action (thus lowering IGF-I production), possibly in addition to antagonizing GH action in other tissues. Available data suggest that women require 1.5 to 2 times more exogenous GH than men. It is likely that the highest GH doses will be needed for women receiving oral estrogens, followed by those receiving transdermal estrogens, followed by nonestrogenized women, followed by men.

Aging Versus Adult GHD

Similarities and Differences Between Aging and Adult GHD

However, despite the similarities between the normal hyposomatomedinemia of aging and genuine organic GHD, there are important differences. First, most organic adult GHD arises from pituitary lesions. In contrast, the loss of GH secretion associated with aging alone results from hormonal changes upstream of the pituitary. Pituitary responsiveness to GHRH persists in aging, although the magnitude of GH release may decline somewhat. The practical implication of this difference is that GH secretagogues should be useful for stimulating GH secretion in normal older people, whereas they are ineffective in most organic forms of adult GHD. A second difference between aging-related GH insufficiency and organic GHD is one of degree. At any age, including advanced ages, individuals with organic GHD have significantly lower measures of basal and stimulated GH secretion than do age-matched normal subjects.^[56-59]

Diagnosing Adult GHD

Unfortunately, distinguishing organic GHD from the hyposomatomedinemia of aging is a challenge. Although GH secretion is lower at any age in patients with organic GHD than in age-matched normal subjects, the spread between these groups diminishes with advancing age, such that GH levels differ by only 13% between elderly adults with GHD and their normal peers.^[58] Thus, confirming GHD in an individual older person may not be possible, especially if only one or no additional pituitary hormones are deficient.^[60] The situation is similar for morbidly obese patients, in whom GH secretion may be suppressed to a similar degree as in organic GHD. Even among people in whom the diagnosis of normal, age-related hyposomatomedinemia is clear, the question remains whether such individuals might benefit from restoration of GH to youthful levels.

Should the Somatopause Be Treated?

Studies of GH Therapy in the Elderly

Although these alterations in body composition are encouraging, it would be more meaningful to document that GH therapy improves functional status in older people, especially because some of the GH-induced increase in LBM arises from water retention. Unfortunately, the data thus far have been disappointing in this regard. Perhaps the most damning study was that of Papadakis et al.^[64] These investigators randomized 52 healthy older men (ages 70-85) with low IGF-I levels to receive either placebo or GH repletion to youthful levels for 6 months. Once again, LBM increased by 4.3% and fat mass decreased by 13.1% in the GH group, while no such changes occurred in controls. However, there were no significant differences between groups in grip strength at the hand or knee or in systemic endurance. Several measurements of cognitive function and mood were performed. Although results varied depending on the test, there was no clear effect of treatment upon these parameters either. The authors concluded that restoration of GH to youthful levels in the elderly for 6 months improves body composition but not functional status. (It is noteworthy that the subjects in this study were in robust health at the outset, making it difficult to detect a GH treatment effect because of "ceiling effects" in the tests employed.)

Several other groups have addressed the question of whether the increased LBM in GH-treated older people translates into more important improvements in muscle strength. This is a particularly germane issue, because muscular weakness is the principal factor limiting independent life for an increasing populace as life spans increase but so do the number of physically compromised years. Although resistance exercise training does increase muscle mass and strength in the elderly, investigators have failed to show that exogenous GH can augment this response.^[65,66]

In view of its anabolic impact on bone, GH is a logical agent to consider for osteoporosis treatment in the elderly. A few small trials have examined this issue in postmenopausal women. All have that found that GH increases markers of bone turnover, but the data on BMD have been unimpressive and conflicting.^[63,66-68] Holloway et al^[69] randomized 27 healthy elderly women (67 ± 3 years) to receive GH or placebo for 6 months. The GH group showed 20-80% increases in markers of both bone formation (osteocalcin) and resorption (urinary hydroxyproline and pyridinoline). These effects persisted for up to 1 year and were most pronounced in subjects not taking supplemental estrogens. Although the placebo group showed a drop of BMD at the hip (3.0% drop at Ward's triangle and 1.7% at the femoral trochanter), the GH group remained stable in this regard. There was no change in BMD at the lumbar spine or other hip sites in either group. The authors concluded that although GH stimulates bone remodeling in postmenopausal women, it exerts at best a protective, rather than an enhancing, effect on BMD.

Because GH increases both bone formation and resorption, it seems logical to investigate it as a remedy for osteoporosis in conjunction with an inhibitor of bone resorption, such as a bisphosphonate. Erdtsieck et al^[70] treated 21 healthy postmenopausal women with pamidronate for one year, either with or without GH therapy for the first 6 months. Pamidronate decreased biochemical markers of bone turnover, an effect that was blocked by concomitant GH treatment. Unfortunately, the net effect was that use of pamidronate alone was associated with a 5% increase in bone mineral mass at the lumbar spine and distal forearm but this desirable effect was ablated by GH coadministration.

GH Secretagogues

The only GH secretagogue presently approved for use as replacement therapy is GHRH(1-29)NH₂ (Geref®, Serono), which has been licensed to treat childhood GHD but is being tested in adults as well. Various GHRPs and nonpeptide GHRP mimetics are also under investigation in elderly subjects (reviewed in ref. 5). Only short-term trials have been published to date, sufficient to assess only hormonal effects. IGF-I has been raised to youthful levels in older individuals with once- or twice-daily subcutaneous injections of GHRH as well as with infusions or daily oral preparations of GHRPs. Data on body composition and functional end points are being compiled. Side effects resulting from inadvertent overtreatment with secretagogues should be less common than with exogenous GH, because of the moderating effects of feedback regulation; studies to date have generally found this to be true. However, some patients do report typical GH-related symptoms of fluid retention as well as allergic reactions at injection sites. Current GH secretagogue formulations are quite short-acting. For these compounds to become clinically useful, we will need to develop more potent preparations, adjuvants to enhance potency, or synergistic GHRH-GHRP combinations.

Summary of GH Treatment for Aging

In short, scientific evidence is currently lacking to support the popular perception of GH as an ergogenic aid in the elderly. Moreover, this population is particularly susceptible to the adverse effects of GH therapy, as well as to the theoretical long-term risks pertaining to cancer and diabetes. Lastly, the cost (~$6000/year for replacement therapy in adults) and inconvenient delivery of GH therapy remain formidable obstacles. Thus, use of GH outside the context of clinical trials is currently not justified for age-related hyposomatomedinemia.

There are several artifactual reasons why studies to date may have failed to demonstrate salutary effects of GH therapy in aging. First, most of the trials were short (<12 months); in adult GHD, improvements in BMD require at least a year of therapy, and increases in muscle strength take 6 to 12 months. Second, several studies had a selection bias for very healthy older subjects, in whom functional improvements are difficult to demonstrate. Third, the high incidence of GH-related side effects (e.g., fluid retention, arthralgias) in elderly subjects led to high dropout rates, which suggests that doses may have been excessive for this older population. Finally, none of the trials was large or long enough to determine whether GH might prevent loss of functional abilities as opposed to actually improving them.

Given its anabolic potencies toward muscle and bone, GH may one day prove efficacious at least for specific short-term uses in the elderly, such as to maintain LBM after injury or surgery or to help rejuvenate the very frail and debilitated.

Recent Reviews

Table 1. Features of Adult GH Deficiency Syndrome and Response to Therapy

Features of Adult GH Deficiency	Improved by GH Replacement?
Fat mass (especially abdominal fat)	Yes
Lean body mass	Yes
Muscle strength	Yes
Cardiac capacity	Yes
Red blood cell volume	Yes
Exercise performance	Yes
Atherogenic lipid profile	Probably
Total cholesterol
LDL-C
Triglycerides
HDL-C
Fibrinogen and PAI-1
Atherosclerosis	No data
Life expectancy	No data
Bone mineral density	Yes (after 1 year of treatment)
Thin, dry skin; poor venous access	Probably
Defective sweating	Yes
Psychosocial problems	Yes
Low self-esteem
Depression
Fatigue or listlessness
Sleep disturbances
Anxiety
Emotional lability and impaired self-control
Social isolation
Poor marital and socioeconomic performance

Adapted from Cummings and Merriam.[5]

Table 2. Recommendations for Adult Growth Hormone Replacement Therapy

Initial dose:150-300 ng SQ qhs (approximately 2-4 mg/kg/d). Start older patients at the low end of this range.

Titrate dose: At monthly or longer intervals, based on clinical response, IGF-I levels, side effects, and individual considerations such as glucose tolerance.

Goal dose: Aim for IGF-I levels at or slightly below the 50th percentile for age and gender unless side effects are significant. Sensitivity to the side effects of GH therapy varies widely; obese and older patients are particularly sensitive.

Contraindications: Active malignancy, benign intracranial hypertension, proliferative diabetic retinopathy. Glucose intolerance is not an absolute contraindication, because although insulin resistance may worsen acutely, reduced central adiposity often improves insulin sensitivity over time. However, these patients require close monitoring, as do individuals with preexisting carpal tunnel syndrome.

Cancer surveillance:Adults receiving GH should receive age- and gender-appropriate periodic cancer screening such as mammography, PSA levels, and colonoscopy. There is currently no consensus on whether enhanced cancer surveillance is appropriate unless a patient has individual risk factors.

Adapted from Cummings and Merriam.[5]

References

1. Raben MS. Clinical use of human growth hormone. N Engl J Med 1962;266:82-86
2. Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age on the 24-hour profile of GH secretion in man: Importance of endogenous estradiol Metab concentrations. J Clin Endocrinol 1987;64:51-58
3. Martha PM Jr, Rogol AD, Veldhuis JD. Alterations in the pulsatile properties of circulating GH concentrations during puberty in boys. J Clin Endocrinol Metab 1989;69:563-570
4. Corpas E, Harman SM, Blackman MR. Human GH and human aging. Endocr Rev 1993;14:20-39
5. Cummings D, Merriam GR. Growth hormone and growth hormone secretagogues in adults. In: Meikle AW, ed. Contemporary Endocrinology: Hormone Replacement Therapy. Totowa, NJ: Humana Press; 1999:61-88
6. Rudman D, Feller AG, Nagraj HS, et al. Effect of human GH in men over 60 years old. N Engl J Med 1990;323:1-6
7. Gelato MC, Merriam GR. Growth hormone-releasing hormone. Annu Rev Physiol 1986;48:569-591
8. Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of GH secretion in experimental animals and the human. Endocr Rev 1998;19:717-797
9. Bowers CY, Veeraragavan K, Sethumadhavan K. Atypical GH releasing peptides. In: Bercu BB, Walker RF. Growth Hormone: Basic and Clinical Aspects. New York: Springer-Verlag; 1994:203-222
10. Patchett AA, Nargund RP, Tata JR, et al. Design and biological activities of L-163,191 (MK-0677), a potent, orally active GH secretagogue. Proc Natl Acad Sci U S A 1995;92:7001-7005
11. Mericq V, Cassorla F, Garcia H, et al. Growth hormone (GH) responses to GH-releasing peptide and to GH-releasing hormone in GH-deficient children. J Clin Endocrinol Metab 1995;80:1681-1684
12. Mericq VG, Salazar T, Avila A, et al. Effects of eight months' treatment with graded doses of growth hormone-releasing peptide in growth hormone-deficient children. J Clin Endocrinol Metab 1998;83:2355-2360
13. Pandya N, DeMott-Friberg R, Bowers CY, et al. Growth hormone-releasing peptide-6 requires endogenous hypothalamic GHRH for maximal GH stimulation. J Clin Endocrinol Metab 1998;83:1186-1189
14. Gelato MC, Malozowski S, Caruso-Nicoletti M, et al. Growth hormone (GH) responses to GHRH during pubertal development in normal boys and girls: Comparison to idiopathic short stature and GH deficiency. J Clin Endocrinol Metab 1986;63:174-179
15. Pavlov EP, Harman SM, Merriam GR, et al. Responses of growth hormone (GH) and somatomedin-C to GH-releasing hormone in healthy aging men. J Clin Endocrinol Metab 1986;62:595-600
16. Chapman IM, Hartman ML, Pezzoli SS, et al. Effect of aging on the sensitivity of GH secretion to insulin-like growth factor-I negative feedback. J Clin Endocrinol Metab 1997;82:2996-3004
17. Ghigo E, Goffi S, Nicolosi M, et al. Growth hormone (GH) responsiveness to combined administration of arginine and GH-releasing hormone does not vary with age in man. J Clin Endocrinol Metab 1990;71:1481-1485
18. Arvat E, Giannoti L, Grottoli S, et al. Arginine and growth hormone-releasing hormone restore the blunted GH-releasing activity of hexarelin in elderly subjects. J Clin Endocrinol Metab 1994;79:1440-1443
19. Kelijman M, Frohman LA. Enhanced growth hormone (GH) responsiveness to GHRH after dietary manipulation in obese and non-obese subjects. J Clin Endocrinol Metab 1988;66:489-494
20. Rose SR, Kibarian M, Gelato MC, et al. Sex steroids increase spontaneous GH secretion in short children. J Pediatr Endocrinol 1988;3:1-5
21. Liu L, Merriam GR, Sherins RJ. Chronic sex steroid exposure increases mean plasma GH concentration and pulse amplitude in men with isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1987;64:651-656
22. Veldhuis JD, Metzger DL, Martha PM, et al. Estrogen and testosterone, but not a nonaromatizable androgen, direct network integration of the hypothalamo-somatotrope (GH)-IGF-1 axis in the human: Evidence from pubertal pathophysiology and sex-steroid hormone replacement. J Clin Endocrinol Metab 1997;82:3414-3420
23. Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age on the 24-hour profile of GH secretion in man: Importance of endogenous estradiol concentrations. J Clin Endocrinol Metab 1987;64:51-58
24. Wilshire GB, Loughlin JS, Brown JR, et al. Diminished function of the somatotropic axis in older reproductive-aged women. J Clin Endocrinol Metab 1995;80:608-613
25. Blake EJ, Adel T, Santoro N. Relationships between insulin-like growth factor-I and estradiol in reproductive aging. Fertil Steril 1997;67:697-701
26. Klein NA, Battaglia DE, Miller PB, Soules MR. Circulating levels of GH, insulin-like growth factor-I, and GH binding protein in normal women of advanced reproductive age. Clin Endocrinol (Oxf) 1996;44:285-292
27. Gelato MC, Pescovitz OH, Cassorla F, et al. Dose-response relationships for the effects of GH releasing factor 1-44 NH₂ in men and women. J Clin Endocrinol Metab 1984;59:197-201
28. Veldhuis JD. Pathophysiology of the neuroregulation of GH secretion in experimental animals and the human. Endocr Rev 1998;19:719-797
29. Bellantoni M, Vittone J, Campfield A, et al. Effects of oral vs. transdermal estrogen on the GH-insulin-like growth factor I axis in younger and older postmenopausal women. J Clin Endocrinol Metab 1996;81:2848-2853
30. Drake W, Coyte D, Camacho H, et al. Optimizing GH replacement therapy by dose titration in hypopituitary adults. J Clin Endocrinol Metab 1998;83:9313-9319
31. Cook DC, Ludlam WH, Cook MB. Route of estrogen administration helps to determine GH replacement dose in GH-deficient adults. J Clin Endocinol Metab 1999;84:3956-3960
32. Burman P, Johansson A, Siegbahn A, et al. Growth hormone deficient men are more responsive to GH replacement than women. J Clin Endocrinol Metab 1997;82:550-555
33. Yakar S, Liu J-L, Stannard B, et al. Normal growth and development in the absence of hepatic insulin-like growth factor-I. Proc Natl Acad Sci U S A 1999;96:7324-7329
34. Khorram O, Laughlin GA, Yen SSC. Endocrine and metabolic effects of long-term administration of [Nle27] GH-releasing hormone (1-29)NH₂ in age-advanced men and women. J Clin Endocrinol Metab 1997;82:1472-1479
35. Merriam GR, Barsness S, Drolet G, et al. Effects of GHRH treatment on 24-hour GH secretion, IGF-I, and body fat in healthy older men and women. Endocrine Society, San Diego, 1999
36. Christ ER, Carroll PV, Russell JDL, Sonksen PH. The consequences of GH deficiency in adulthood, and the effects of GH replacement. Schweiz Med Wochenschr 1997;127:1440-1449
37. Cuneo RC, Salomon F, McGauley GA, Sonksen PH. The GH deficiency syndrome in adults. Clin Endocrinol (Oxf) 1992;37:387-397
38. Labram EK, Wilkin TJ. Growth hormone deficiency in adults and its response to GH replacement. QJM 1995;88:391-399
39. Ros'en T, Johannsson G, Johansson JO, Bengtsson BA. Consequences of GH deficiency in adults and the benefits and risks of recombinant human GH treatment. Horm Res 1995;43:93-99
40. Jorgensen JO, Muller J, Moller J, et al. Adult GH deficiency. Horm Res 1994;42:235-241
41. Lieberman SA, Hoffman AR. Growth hormone deficiency in adults: Characteristics and response to GH replacement. J Pediatr 1996;128:S58-S60
42. Ros'en T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990;336:285-288
43. Bates AS, Van't HW, Jones PJ, Clayton RN. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 1996;81:1169-1172
44. Bengtsson BA. The consequences of GH deficiency in adults. Acta Endocrinol (Copenh) 1993;2:2-5
45. Harris MI. Epidemiology of diabetes mellitus among the elderly in the United States. Clin Geriatr Med 1990;6:703-719
46. Lamberts SWJ, Van den Beld AW, Van der Lely AJ. The endocrinology of aging. Science 1997;278:419-424
47. Ezzat S, Melmed S. Clinical review 18: Are patients with acromegaly at increased risk for neoplasia? J Clin Endocrinol Metab 1991;72:245-249
48. Brunner JE, Johnson CC, Zafar S, et al. Colon cancer and polyps in acromegaly: Increased risk associated with family history of colon cancer. Clin Endocrinol (Oxf) 1990;32:65-71
49. Hankinson SE, Willett WC, Colditz GA, et al. Circulating concentrations of IGF-1 and risk of breast cancer. Lancet 1998;351:1393-1396
50. Chan JM, Stampfer MJ, Giovanucci E, et al. Plasma IGF-1 and prostate cancer risk: A prospective study. Science 1998;279:563-566
51. Holly J. IGF-1 and new opportunities for cancer prevention. Lancet 1998;351:1373-1375
52. Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency: Summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 1998;83:379-381
53. Takala J, Ruokonen E, Webster NR, et al. Increased mortality associated with GH treatment in critically ill adults. N Engl J Med 1999;341:785-792
54. Iranmanesh A, Lizarralde G, Velduis JD. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. J Clin Endocrinol Metab 1991;73:1081-1088
55. Abbasi AA, Drinka PJ, Mattson DE, Rudman D. Low circulating levels of insulin-like growth factors and testosterone in chronically institutionalized elderly men. J Am Geriatr Soc 1993;41:975-982
56. Reutens AT, Veldhuis JD, Hoffman DM, et al. A highly sensitive GH ELISA uncovers increased contribution of a tonic mode of GH secretion in adults with organic GH deficiency. J Clin Endocrinol Metab 1996;81:1591-1597
57. Toogood AA, O'Neill PA, Shalet SM. Beyond the somatopause: GH deficiency in adults over the age of 60 years. J Clin Endocrinol Metab 1996;81:460-465
58. Toogood AA, Nass RM, Pezzoli SS, et al. Preservation of GH pulsatility despite pituitary pathology, surgery, and irradiation. J Clin Endocrinol Metab 1997;82:2215-2221
59. Hoffman DM, O'Sullivan AJ, Baxter RC, Ho KKY. Diagnosis of growth-hormone deficiency in adults. Lancet 1994;343:1064-1068
60. Shalet SM, Toogood A, Rahim A, Brennan BMD. The diagnosis of GH deficiency in children and adults. Endocr Rev 1998;19:203-223
61. Rudman D, Feller AG, Nagraj HS, et al. Effects of human GH in men over 60 years old. N Engl J Med 1990;323:1-6
62. Rudman D, Feller AG, Cohn L, et al. Effects of human GH on body composition in elderly men. Horm Res 1991;36(suppl):73-81
63. Thompson JL, Butterfield GE, Marcus R, et al. The effects of recombinant human insulin-like growth factor-I and GH on body composition in elderly women. J Clin Endocrinol Metab 1995;80:1845-1852
64. 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;124:708-716
65. Taaffe DR, Jin IH, Vu TH, et al. Lack of effect of recombinant human growth hormone (GH) on muscle morphology and GH-insulin-like growth factor expression in resistance-trained elderly men. J Clin Endocrinol Metab 1996;81:421-425
66. Yarasheski KE, Campbell JA, Kohrt WM. Effect of resistance exercise and GH on bone density in older men. Clin Endocrinol 1997;47:223-229
67. Marcus R, Butterfield G, Holloway L, et al. Effects of short term administration of recombinant human GH to elderly people. J Clin Endocrinol Metab 1990;70:519-527
68. Aloia JF, Zanzi I, Ellis K, et al. Effects of GH in osteoporosis. J Clin Endocrinol Metab 1976;43:992-999
69. Holloway L, Butterfield G, Hintz RL, et al. Effects of recombinant human GH on metabolic indices, body composition, and bone turnover in healthy elderly women. J Clin Endocrinol Metab 1994;79:470-479
70. Erdtsieck RJ, Pols HA, Valk NK, et al. Treatment of post-menopausal osteoporosis with a combination of GH and pamidronate: A placebo controlled trial. Clin Endocrinol (Oxf) 1995;43:557-565
71. Marcus R, Hoffman AR. Growth hormone as therapy for older men and women. Annu Rev Pharmacol Toxicol 1998;38:45-61
72. Merriam GR, Cassorla F. Clinical and physiological studies with growth hormone-releasing hormone. In: Smith RG, Thorner MO, eds. Human Growth Hormone: Research and Clinical Practice. Totowa, NJ: Humana Press; 1999: 297-313
73. Martin FC, Yeo A-L, Sonksen PH. Growth hormone secretion in the elderly: Aging and the somatopause. Baillieres Clin Endocrinol Metab 1997;11:223-250
74. Kojima M, Hosoda H, Date Y, Nakagato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656-660

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