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Original Contribution |

Growth Hormone and Sex Steroid Administration in Healthy Aged Women and Men:  A Randomized Controlled Trial FREE

Marc R. Blackman, MD; John D. Sorkin, MD, PhD; Thomas Münzer, MD; Michele F. Bellantoni, MD; Jan Busby-Whitehead, MD; Thomas E. Stevens, MD; Jocelyn Jayme, MD; Kieran G. O'Connor, MD; Colleen Christmas, MD; Jordan D. Tobin, MD; Kerry J. Stewart, EdD; Ernest Cottrell, BS; Carol St. Clair, MS; Katharine M. Pabst, CRNP, MPH; S. Mitchell Harman, MD, PhD
[+] Author Affiliations

Author Affiliations: Divisions of Endocrinology and Metabolism (Drs Blackman and Jayme, Mr Cottrell, and Mss St. Clair and Pabst), Cardiology (Dr Stewart), and Geriatric Medicine and Gerontology (Drs Bellantoni, Busby-Whitehead, Stevens, O'Connor, and Christmas), Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md; the Endocrine (Drs Münzer and Harman), Metabolism (Dr Sorkin), and Applied Physiology (Dr Tobin) Sections, Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, and National Center for Complementary and Alternative Medicine (Dr Blackman and Ms Pabst), National Institutes of Health, Bethesda, Md; Department of Medicine, University of Maryland School of Medicine, Baltimore (Dr Sorkin and Ms St. Clair); Burgerspital, St Gallen, Switzerland (Dr Münzer); Division of Geriatric Medicine, University of North Carolina School of Medicine, Chapel Hill (Dr Busby-Whitehead); Division of Geriatric Medicine, University of Southern Alabama School of Medicine, Mobile (Dr Stevens); Louth Hospital, County Louth, Ireland (Dr O'Connor); and Kronos Research Institute, Phoenix, Ariz (Dr Harman).


JAMA. 2002;288(18):2282-2292. doi:10.1001/jama.288.18.2282.
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Published online

Context Hormone administration to elderly individuals can increase lean body mass (LBM) and decrease fat, but interactive effects of growth hormone (GH) and sex steroids and their influence on strength and endurance are unknown.

Objective To evaluate the effects of recombinant human GH and/or sex steroids on body composition, strength, endurance, and adverse outcomes in aged persons.

Design, Setting, and Participants A 26-week randomized, double-blind, placebo-controlled parallel-group trial in healthy, ambulatory, community-dwelling US women (n = 57) and men (n = 74) aged 65 to 88 years recruited between June 1992 and July 1998.

Interventions Participants were randomized to receive GH (starting dose, 30 µg/kg, reduced to 20 µg/kg, subcutaneously 3 times/wk) + sex steroids (women: transdermal estradiol, 100 µg/d, plus oral medroxyprogesterone acetate, 10 mg/d, during the last 10 days of each 28-day cycle [HRT]; men: testosterone enanthate, biweekly intramuscular injections of 100 mg) (n = 35); GH + placebo sex steroid (n = 30); sex steroid + placebo GH (n = 35); or placebo GH + placebo sex steroid (n = 31) in a 2 × 2 factorial design.

Main Outcome Measures Lean body mass, fat mass, muscle strength, maximum oxygen uptake (O2max) during treadmill test, and adverse effects.

Results In women, LBM increased by 0.4 kg with placebo, 1.2 kg with HRT (P = .09), 1.0 kg with GH (P = .001), and 2.1 kg with GH + HRT (P<.001). Fat mass decreased significantly in the GH and GH + HRT groups. In men, LBM increased by 0.1 kg with placebo, 1.4 kg with testosterone (P = .06), 3.1 kg with GH (P<.001), and 4.3 kg with GH + testosterone (P<.001). Fat mass decreased significantly with GH and GH + testosterone. Women's strength decreased in the placebo group and increased nonsignificantly with HRT (P = .09), GH (P = .29), and GH + HRT (P = .14). Men's strength also did not increase significantly except for a marginally significant increase of 13.5 kg with GH + testosterone (P = .05). Women's O2max declined by 0.4 mL/min/kg in the placebo and HRT groups but increased with GH (P = .07) and GH + HRT (P = .06). Men's O2max declined by 1.2 mL/min/kg with placebo and by 0.4 mL/min/kg with testosterone (P = .49) but increased with GH (P = .11) and with GH + testosterone (P<.001). Changes in strength (r = 0.355; P<.001) and in O2max (r = 0.320; P = .002) were directly related to changes in LBM. Edema was significantly more common in women taking GH (39% vs 0%) and GH + HRT (38% vs 0%). Carpal tunnel symptoms were more common in men taking GH + testosterone (32% vs 0%) and arthralgias were more common in men taking GH (41% vs 0%). Diabetes or glucose intolerance occurred in 18 GH-treated men vs 7 not receiving GH (P = .006).

Conclusions In this study, GH with or without sex steroids in healthy, aged women and men increased LBM and decreased fat mass. Sex steroid + GH increased muscle strength marginally and O2max in men, but women had no significant change in strength or cardiovascular endurance. Because adverse effects were frequent (importantly, diabetes and glucose intolerance), GH interventions in the elderly should be confined to controlled studies.

Figures in this Article

The extent to which reduced function of the growth hormone (GH) and insulinlike growth factor I (IGF-I) axis in aged women and men,1,2 estrogen deficiency in postmenopausal women,3 and decreases in testosterone4 in older men contribute to decrements in skeletal muscle mass and strength5 and increases in total and intra-abdominal fat6 remains uncertain. The latter may be precursors of clinical conditions such as musculoskeletal frailty with reduced physical function,7 insulin resistance, type 2 diabetes, and cardiovascular disease.8

In nonelderly GH-deficient adults, sarcopenia, central obesity, and other features resembling the aging phenotype are improved by long-term hormone replacement with recombinant human GH (rhGH).9 A study10 in which 6 months of rhGH treatment increased lean body mass (LBM) and reduced body fat in healthy aged men stimulated widespread interest in whether GH treatment might attenuate physical and functional concomitants of aging. Subsequent studies have confirmed that short-term GH replacement in older persons improves body composition,2 but studies have not demonstrated gains in muscle strength or cardiovascular endurance. In older adults GH administration commonly produces adverse effects, including carpal tunnel syndrome, peripheral edema, arthralgias, and glucose intolerance.11,12

Despite the paucity of efficacy and safety data, there is extensive off-label prescription of GH for healthy older persons to reverse effects of the "somatopause,"13 with little emphasis given to actual and potential adverse effects.14

Hormone replacement therapy (HRT) in healthy postmenopausal women decreases abdominal visceral fat and improves plasma lipid profiles.15 Although epidemiologic studies suggested that HRT reduces coronary artery disease (CAD) risk, a recent controlled trial calls this into question.16 In comparison, testosterone treatment improves body composition and muscle strength in nonelderly hypogonadal men17 and body composition in older men.18

Changes in body composition and function during aging may result in part from the interactive effects of decreases in both GH and sex steroids.19 We previously demonstrated in this population that GH and testosterone did not improve bone mineral density20 or decrease visceral fat but reduced subcutaneous fat.21 However, the most important issues clinically—effects on muscle strength, cardiovascular endurance, LBM, and total body fat, as well as adverse effects—have not been assessed. We evaluated the effects of 26 weeks of rhGH and gonadal steroid administration, alone and in combination, on body composition, muscle strength, cardiovascular endurance, and adverse effects in healthy older women and men.

Study Subjects

Ambulatory, community-dwelling US women and men, ranging in age from 65 to 88 years, were recruited by mailings and advertisements between June 1992 and July 1998. All were healthy as verified by screening history and physical examination, routine blood studies, and urinalysis. No participant had diabetes, depression, untreated thyroid disease, symptomatic or occult CAD demonstrated by graded treadmill exercise test, liver or renal disease, or cancer other than basal cell skin cancer. Participants did not smoke, drank less than 30 g/d of alcohol, and took no medications interfering with the GH or gonadal steroid axes. Volunteers were selected to have serum IGF-I levels of 230 ng/mL or lower (≥1 SD below the mean for healthy adults aged 20-35 years). Women were postmenopausal (follicle-stimulating hormone levels, ≥30 U/L; estradiol [E2] levels, ≤30 pg/mL [≤110 pmol/L]) and had not used HRT for at least 3 months before the study. Eighteen women had taken HRT previously, of whom 4 discontinued HRT 3 months before randomization. Men had screening serum testosterone levels of 470 ng/dL (16.3 nmol/L) or lower. No man had previously taken testosterone replacement. The protocol was approved by the combined institutional review board of the Johns Hopkins Bayview Medical Center (JHBMC) and the Intramural Research Program, National Institute on Aging. Written informed consent was obtained from each participant.

Study Protocol

The 26-week study used a randomized, double-blind, placebo-controlled, parallel-group 2 × 2 factorial design. Volunteers were randomized to receive rhGH plus placebo sex steroid (GH); sex steroid plus placebo rhGH (HRT for women, testosterone for men); rhGH plus sex steroid(s) (GH + HRT for women, GH + testosterone for men); or placebo rhGH plus placebo sex steroid(s) (placebo). Randomization was completed using the "RAND" function in Excel (Microsoft Corp, Redmond, Wash). There was no stratification or blocking.

At baseline, participants were admitted to the General Clinical Research Center at JHBMC at 6 PM on day 1. Height was measured using a standing stadiometer and weight with a calibrated clinical scale. At 8 AM on day 2, after an overnight fast, blood was collected for measurements of serum IGF-I, E2 in women (to confirm menopause), and testosterone in men. On days 2 and 3, the primary outcome measurements of muscle strength, O2max, and body composition were assessed as described below. Participants were instructed in self-administration of study medications and discharged on the afternoon of day 3.

Participants were advised to maintain their usual level of physical activity and to consume their customary diets during the 26-week protocol. Physical activity patterns were assessed using the Physical Activity Scale for the Elderly (PASE),22 and 3-day diet histories were obtained by a nutritionist. At week 26, all baseline procedures were repeated.

Administration of Hormones

On the day of discharge, women received the first of 6 one-month supplies of 100 µg/d of estradiol or placebo transdermal patches (Estraderm; Novartis, Basel, Switzerland), plus 10 mg of medroxyprogesterone acetate (Provera; Pharmacia & Upjohn, Peapack, NJ) or placebo tablets. Women applied a new patch twice weekly and took medroxyprogesterone 10 mg/d or placebo for the last 10 days of each 28-day cycle. A nurse not involved in assessment of end points or adverse effects administered testosterone to men as biweekly intramuscular injections of 100 mg of testosterone enanthate in oil (Delatestryl Injection; Bio-Technology General Corp, Iselin, NJ) or the same volume of sterile saline placebo. Men and women were also given their first subcutaneous injections of GH (Nutropin; Genentech Inc, South San Francisco, Calif) or saline placebo at the time of discharge. All participants self-administered GH or placebo injections 3 times per week (Monday, Wednesday, and Friday) 1 hour before bedtime.

During year 1 the starting dose of GH was 30 µg/kg,10 after which it was reduced to 20 µg/kg due to the high frequency of adverse effects observed. In women, 2 in the placebo, 2 in the HRT, 4 in the GH, and 3 in the GH + HRT groups started with injection volumes corresponding to 30 µg/kg. In men, 3 in the placebo, 2 in the testosterone, 3 in the GH, and 4 in the GH + testosterone groups started with injection volumes corresponding to 30 µg/kg. In addition, 2 women and 6 men treated with GH alone, 1 woman in the GH + HRT group, and 4 men in the GH + testosterone group required GH dose reductions. Mean daily GH doses were, for women in the GH and GH + HRT groups, respectively, 9.3 (2.2) and 10.0 (1.5) µg/kg/d, and for men in the GH and GH + testosterone groups, respectively, 9.2 (2.1) and 8.8 (1.8) µg/kg/d. Doses did not differ significantly within (women, P = .23; men, P = .81) or between (P = .54) sexes.

Assays

Serum IGF-I levels were measured by radioimmunoassay (normal range, 250-750 ng/mL) after acid-ethanol extraction (Endocrine Sciences Laboratories, Calabasas Hills, Calif), with a sensitivity of 30 ng/mL, and intra-assay and interassay coefficients of variation, respectively, of 5.9% and 7.3% at 289 ng/mL and 4.6% and 6.3% at 591 ng/mL.

Serum levels of E2 and testosterone were measured in duplicate by radioimmunoassay using commercial kits (Diagnostic Products Corporation, Los Angeles, Calif). The E2 assay (normal range, 49-199 pg/mL [182-730 pmol/L]) sensitivity was 20 pg/mL (73 pmol/L), with intra-assay coefficients of variation of 8.3%, 2.5%, and 5.3%, respectively, at mean E2 concentrations of 48 pg/mL (176 pmol/L), 119 pg/mL (437 pmol/L), and 187 pg/mL (686 pmol/L) and interassay coefficients of variation of 8.9%, 6.0%, and 6.8%, respectively, at mean E2levels of 29 pg/mL (106 pmol/L), 99 pg/mL (363 pmol/L), and 186 pg/mL (683 pmol/L). The testosterone assay (normal range, 288-1210 ng/dL [10-42 nmol/L]) sensitivity was 10 ng/dL (0.35 nmol/L), with intra-assay coefficients of variation of 11.7%, 6.7%, 1.5%, and 3.1% at mean testosterone concentrations of 60 ng/dL (2.08 nmol/L), 300 ng/dL (10.4 nmol/L), 596 ng/dL (20.7 nmol/L), and 997 ng/dL (34.6 nmol/L), respectively. Interassay coefficients of variation were 9.5%, 5.8%, 5.7%, and 1.4% at mean testosterone concentrations of 75 ng/dL (2.6 nmol/L), 294 ng/dL (10.2 nmol/L), 703 ng/dL (24.4 nmol/L), and 1032 ng/dL (35.8 nmol/L), respectively.

Glucose was measured using a routine glucose oxidase method in the JHBMC clinical laboratory.

Body Composition, Muscle Strength, and

Lean body mass and total fat mass were measured by dual-energy x-ray absorptiometry (DXA) (Lunar model DPX-L; Lunar Radiation, Madison, Wis) using a previously validated 3-compartment model23 that excludes bone from the LBM compartment. Total body scans were analyzed using Lunar software version 3.65u. The scanner was calibrated daily according to the manufacturer's recommendations. The variability of the DXA scanner for both LBM and fat mass in our laboratory was approximately 1%.24

Muscle strength was assessed by a standard 1-repetition maximum (1-RM) procedure25 using 4 upper body (bench press, upright row, arm curl, and arm extension) and 2 lower body (leg press and leg curl) stations on an exercise machine (Universal Fitness, West Point, Miss). Participants were familiarized with each exercise by performing several repetitions using unloaded equipment, after which a 1-RM weight was estimated by adding 2.5-lb (1.125-kg) increments until a full-range lift could not be completed. The highest weight lifted was the 1-RM. Participants rested as needed between attempts and were monitored continuously with electrocardiography (ECG). Most individuals reached 1-RM in 3 to 4 attempts so that progressive fatigue was not a confounding factor. Total body strength was calculated as the sum of all 6 1-RM values.

Cardiovascular endurance (maximum aerobic capacity [O2max]) was assessed as maximum oxygen uptake during a symptom-limited graded treadmill test using a modified Bruce protocol.26 The test was performed to maximal volitional fatigue, claudication, or cardiac end points such as angina, significant ST depression, high-grade arrhythmias, or hypotension. Maximal oxygen uptake, ventilation, CO2 production, and anaerobic threshold were determined using a commercial metabolic analysis system (Medical Graphics CardiO2,St Paul, Minn). Data were expressed as milliliter of oxygen consumed per kilogram of body weight. The ECG was monitored continuously, and blood pressure, heart rate, and a 12-lead ECG were recorded during exercise.

Assessment of Adverse Effects

Participants were seen weekly for assessment of adverse effects and measurement of body weight, temperature, blood pressure, and pulse. Every 4 weeks the same physician or nurse practitioner conducted a detailed assessment including a structured questionnaire seeking symptoms of carpal tunnel syndrome, joint pain, and headaches or visual changes and a physical examination assessing the optic fundi, peripheral sensation in the hands, joint swelling or tenderness, and dependent edema. For reporting purposes, we defined edema as swelling of a lower extremity, with evident pitting on moderate digital pressure, with or without symptoms; carpal tunnel symptoms as complaints of numbness or paresthesia of hands on more than 2 occasions with no precipitating event; and arthralgia as new or increased joint pain, stiffness, or tenderness. Blood was collected after an overnight fast for serum glucose, IGF-I, testosterone (1 week after most recent biweekly injection), E2, and hematocrit determinations. Glucose intolerance and diabetes were defined using revised American Diabetes Association criteria.27 Active medication doses were reduced in 25% decrements by an unblinded safety monitor, based on adverse effects and/or elevations of serum IGF-I higher than 350 ng/mL, testosterone higher than 807 ng/dL (28 nmol/L), or E2 higher than 55 pg/mL (202 pmol/L). For each dose reduction, a similar reduction was instituted for a participant taking the corresponding placebo.

Serum prostate-specific antigen (PSA) levels were determined at baseline and follow-up in the clinical laboratory of the JHBMC by monoclonal radioimmunoassay (Tandem-R; Hybritech Inc, San Diego, Calif). Men also completed a prostate symptom questionnaire (International Prostate Symptom Scale).28

Statistical Analysis

Power analyses indicated that a group size of 20 would detect a 25% difference at the .05 level in muscle strength and a 12% difference in O2max. Additional analyses revealed that group sizes of 10 would detect 10% changes in body composition end points at the .01 level.

Data were analyzed using SAS statistical software versions 6.12 and 8.2 (SAS Institute Inc, Cary, NC). All data are expressed as the mean (SE) values. Primary analyses were by intention to treat, carrying forward the last recorded data points for each variable from the 6 individuals (4.7%) who dropped out.

Sex differences for each variable at baseline or after 26 weeks were assessed by 1-way analysis of variance. Significance of changes (26-week minus baseline values) in LBM, total body fat, muscle strength, and O2max were calculated by 1-way analysis of covariance adjusted for age, value of the dependent variable at baseline, and treatment group. Each treatment group was compared with the placebo group; the method of Dunnett29 was used to control for multiple comparisons. Separate models were analyzed for men and women.

To investigate relationships between hormones and other outcome measures we calculated Pearson correlation coefficients between variables at baseline and, in separate analyses, between changes in variables. Relationships were assessed in women and men together when slopes of regressions in each sex showed no significant differences. Adverse event frequencies were compared between treatment and placebo groups separately for women and men by Fisher exact test in all participants randomized. Differences between cumulative average rhGH doses per day in the groups receiving GH were assessed by Mann-Whitney U tests comparing men vs women and individuals of each sex receiving GH alone vs GH + sex steroid. P≤.05 was considered significant.

Participant Characteristics

The study population included 57 women and 74 men aged 65 through 88 years (mean [SE], 72 [0.4] years). Four women and 2 men discontinued before 26 weeks (dropout rate, 4.7%): 2 women (both in the GH + HRT group) due to adverse effects consistent with estrogen use (vaginal bleeding, breast tenderness), 2 women (1 each in the placebo and GH groups) for reasons unrelated to adverse effects, and both men (1 each in the GH and GH + testosterone groups) due to GH-related adverse effects (arthralgias, carpal tunnel symptoms, and edema) (Figure 1). Mean baseline ages did not differ by sex, but weight, body mass index, and IGF-I levels were higher in men (Table 1). Within-sex group characteristics did not differ significantly (Table 1).

Figure 1. Flow of Patients Through the Study
Graphic Jump Location
Table Graphic Jump LocationTable 1. Baseline Characteristics by Treatment Group*

Three-day diet histories and self-reported physical activity (PASE) did not differ before or after treatment in either sex (data not shown).

Levels of IGF-I and Sex Steroids

Levels of IGF-I increased in women and men given GH (P<.001), with no significant differences between the GH and GH + sex steroid–treated women (P = .72) or men (P = .18). Levels of IGF-I were higher in GH-treated (mean [SE], 244 [5] vs 192 [4] ng/mL; P<.001) and non-GH–treated (138 [3] vs 109 [3] ng/mL; P = .001) men vs women. Neither placebo nor sex steroids significantly changed IGF-I levels in either sex (Figure 2A and 2B).

Figure 2. Effects of 26 Weeks of Hormone or Placebo Administration
Graphic Jump Location
Effects of administration of growth hormone (GH), hormone replacement therapy, and/or placebo to women (A and C) and GH, testosterone, and/or placebo to men (B and D) 65 years or older and sequential serum levels of insulinlike growth factor I (IGF-I) (A and B), estradiol (C), and testosterone (D). Values are presented as mean (SE). To convert estradiol to pmol/L, multiply data by 3.67; to convert testosterone to nmol/L, multiply data by 0.0347. Curves were compared using repeated measures analysis of variance with P value estimates shown in the plots calculated for multiple comparisons using a post hoc Scheffé analysis. The time point (−4) before 0 weeks (baseline) represents the screening visit.

In women, serum E2 levels increased after administration of HRT (P<.001) and GH + HRT (P<.001). In men, serum testosterone levels increased after administration of testosterone (P<.001) and GH + testosterone (P = .002), respectively. There were no effects of coadministration of GH in women (P = .97) or men (P = .44) on levels attained. Neither placebo nor GH treatment significantly changed sex steroid levels in either sex (Figure 2C and 2D).

Body Composition

Lean body mass was greater (P<.001) in men than in women at baseline and after 26 weeks (Table 2). At baseline, there were no significant group differences in LBM in women, whereas in men baseline LBM in the testosterone group was significantly lower than that in the placebo group (P = .003). In women, compared with placebo LBM increased significantly with GH and GH + HRT but not HRT, with no significant differences between GH-treated groups. In men, LBM increased significantly with GH and GH + testosterone with a trend toward a significant increase after testosterone (P = .06). The increase with GH + testosterone was greater than that for testosterone (P<.001) but not significantly greater than with GH alone (P = .06). In a secondary "as-treated" analysis of individuals completing 26 weeks, LBM increased significantly with testosterone by 2.9% (P = .04).

Table Graphic Jump LocationTable 2. Effects of Treatments on Lean Body Mass and Fat Mass as Demonstrated by DXA*

Total fat mass was greater in women than in men at 26 weeks (P = .02) but not at baseline (P = .08) (Table 2). At baseline, there were no significant within-sex group differences in fat mass. In women, fat mass decreased similarly with GH and GH + HRT but not HRT. In men, fat mass decreased significantly with GH and GH + testosterone but not testosterone. The decrease with GH + testosterone was greater than that for testosterone (P = .001) and was marginally greater than for GH (P = .05). In a secondary as-treated analysis of individuals completing 26 weeks, decrease in fat was greater with GH + testosterone than with testosterone (P<.001) or GH (P = .04).

Muscle Strength

Before and after treatment, strength (Table 3) was greater in men than in women (P<.001), with no significant group differences at baseline in either sex. At 26 weeks, women's strength did not change significantly in any treatment group, whereas in GH + testosterone–treated men, the increase in strength of 6.8% was marginally significant.

Table Graphic Jump LocationTable 3. Effects of Hormone Administration on Total Body Strength*
Aerobic Capacity

Before and after treatment, mean values for O2max (Table 4) were higher in men than in women (P<.001), with no baseline within-sex group differences. In women O2max did not increase, whereas it increased by 8.3% in GH + testosterone–treated men.

Table Graphic Jump LocationTable 4. Effects of Hormone Treatments on Maximal Oxygen Capacity (O2max) by Graded Treadmill Exercise Testing*
Serum Hormone Levels, Body Composition, and Aerobic Capacity

At baseline, in all women and men combined, LBM (r = 0.261, P = .003) and strength (r = 0.306, P<.001), but not fat mass (r = 0.010, P = .91) or O2max (r = 0.088, P = .33), were directly related to IGF-I levels. Strength (r = 0.893, P<.001) and absolute O2max (r = 0.845, P<.001) were also directly related to LBM. After 26 weeks, changes in LBM (r = 0.404, P<.001) and in strength (r = 0.196, P = .04), but not changes in O2max (r = 0.083, P = .36), were directly related to changes in IGF-I. Changes in fat mass (r = −0.347, P = .001) were inversely related to changes in IGF-I. Changes in strength (r = 0.255, P = .005) and in O2max (r = 0.324, P<.001) were directly related to changes in LBM (Figure 3). These baseline and posttreatment relationships were similar in women and men, with no significant sex differences in slopes of corresponding regression equations (data not shown). In men, baseline and posttreatment relationships of testosterone with LBM, fat mass, strength, or O2max were not significant (data not shown).

Figure 3. Bivariate Plots of the Relationships of Changes in Lean Body Mass (LBM) With Changes in Total Body Strength and O2max During 26 Weeks of Hormone or Placebo Administration
Graphic Jump Location
r and P values were calculated by linear regression for the combined groups of women and men. GH indicates growth hormone. O2max is measured as milliliters per minute per kilogram of body weight.
Adverse Effects

Peripheral edema, carpal tunnel symptoms, and arthralgias occurred in 24% to 46% of GH-treated participants (Table 5). Edema and arthralgias were more common in GH-treated women. In men, carpal tunnel symptoms were more frequent in the GH + testosterone group and arthralgias in the GH group. No man taking GH + testosterone reported arthralgias, in contrast to 7 (41%) receiving GH. Testosterone administration did not significantly increase these adverse effects.

Table Graphic Jump LocationTable 5. Common Adverse Effects During 26 Weeks of Treatment*

Weight changes of more than 3 kg or changes in mean body weight did not differ significantly in any treatment group (data not shown).

In individuals taking GH without or with sex steroid, the number per participant of arthralgias, edema, and carpal tunnel symptoms in women (r = 0.529, P<.001) and in men (r = 0.412, P<.001) were directly related to mean IGF-I levels during treatment. Occurrence of these adverse effects was similarly correlated with the maximum level of IGF-I and significantly but less strongly with changes in IGF-I levels (data not shown).

Vaginal bleeding occurred in 29% of women receiving HRT (P = .04), 65% of women receiving GH + HRT (P<.001), 6% receiving GH (P = .48), and none in the placebo group.

There were no significant increases in the incidence of headaches or changes in the optic fundi. In men there were no significant increases in gynecomastia (Table 5), symptoms of prostatism, or excessive daytime sleepiness. Uncommonly reported (<5%) adverse effects included hematochezia; foot, hand, or testis swelling; new heart murmurs; urinary frequency; and transient erectile dysfunction. One woman (placebo group) had a basal cell skin cancer and 1 man (testosterone group) was diagnosed as having a dysplastic junctional nevus, which were resected surgically.

Blood Pressure and Pulse Rates

Systolic and diastolic blood pressures and mean pulse rates did not change significantly in any treatment group (data not shown).

Blood Glucose and Diabetes

As illustrated in Table 6, at baseline none of the women or men met the revised27 ADA criteria for diabetes mellitus, but 3 men did so for fasting glucose intolerance. Sex steroid administration did not increase rates of fasting glucose intolerance or diabetes in women or men. However, diabetes developed in 5 men receiving GH and 1 man not taking GH (P = .06), and diabetes or fasting glucose intolerance occurred in 18 GH-treated men vs 7 not receiving GH (P = .006). Fasting glucose returned to normal values 2 to 6 weeks after discontinuation of treatment in diabetic men.

Table Graphic Jump LocationTable 6. Rates of Fasting Glucose Intolerance and Diabetes by Treatment Group*
Hematocrit

In men, there were no significant increases in hematocrit in any hormone-treated group. No man developed hematocrit values higher than 55%. In men receiving testosterone, there were no significant relationships between maximum value or maximum change in hematocrit and measures of testosterone (data not shown).

Prostate

Mean serum PSA levels did not change significantly in any treatment group (data not shown). After testosterone administration, 2 men exhibited increases in PSA greater than 1.0 ng/mL, but neither had prostate carcinoma on fine needle biopsy. There were no significant changes in International Prostate Symptom Scale scores or increased complaints of prostatism symptoms in any group.

During 26 weeks of GH and/or sex steroid treatment, IGF-I, E2, and testosterone levels increased into the mid-normal range for young women and men. In both sexes, GH increased LBM and decreased fat mass. Among men taking GH + testosterone, strength increased marginally and O2max increased significantly. Changes in muscle strength and O2max were directly related to changes in LBM. In men, GH elicited greater responses in IGF-I and body composition than in women. GH + testosterone elicited greater increases in LBM and O2max and decreases in fat than did testosterone alone, and GH + testosterone produced marginally greater responses than did GH alone. In women, changes were similar after GH + HRT or GH alone. To our knowledge, these findings are novel.

Like others,10,30 we found that GH significantly increased IGF-I in elderly individuals and that IGF-I increased more in older men than in older women, a sex difference also observed after GH administration in nonelderly GH-deficient adults.9,31 In the women in our study, HRT did not significantly affect IGF-I, consistent with prior reports using similar doses of transdermal estrogens.32 In contrast, previous studies have shown that oral33 or high-dose transdermal34 estrogen decreases IGF-I. In the men in our study, IGF-I increased similarly with GH and GH + testosterone, but not with testosterone alone. Data from prior studies21,35 suggest that the age-related decline in testosterone in men contributes to reduction in GH secretion and that the latter can be partially reversed by testosterone in doses higher than those we used. Growth hormone alone did not significantly alter sex steroids in either sex, suggesting that the GH doses used did not stimulate sex steroid production by the senescent gonad.

We found greater GH-mediated responses in LBM and fat in aged men than in women, consistent with prior reports in GH-deficient younger adults.9 In women, HRT treatment did not increase LBM or decrease fat significantly. The effects of HRT on body composition are controversial, although previous studies suggest that postmenopausal progestin can reduce tissue responsiveness to estrogens during HRT.36,37 Low-dose testosterone did not elicit significant increases in LBM or decreases in fat in aged men in our study, in contrast to significant changes reported using higher doses of parenteral or transdermal testosterone.18,38 The effects of GH + testosterone on LBM and fat appeared additive, suggesting that they resulted from submaximal responses mediated by similar mechanisms,39 or that the mechanisms differed but were complementary.40

In the men in our study, the magnitudes of the increases in LBM and decreases in fat following GH + testosterone treatment were similar to those reported after 6 months of exercise training 3 times per week41 and greater than those observed after training once per week.42 This finding is noteworthy because participants reported no changes in their dietary or physical activity patterns, as confirmed by dietary histories and PASE surveys. Body composition changes observed could be of clinical significance if they were associated with proportional improvements in strength, performance, and cardiac risk factors. However, GH- and/or sex steroid–mediated increases in LBM demonstrated on DXA must be interpreted with caution because they may reflect changes in cell mass or extracellular water. Isotopic studies reveal that decreased LBM in nonelderly GH-deficient adults results from reductions in cell mass and extracellular water, and that both components increase after GH replacement.9 We are unaware of analogous studies in somatopausal elderly individuals. The observed correlations of increases in strength and O2max with changes in LBM suggest that, in the current study, GH produced increases in functional muscle mass.

We observed a 6.8% increase in strength in men treated with GH + testosterone, which was of marginal statistical significance. Most30,43 but not all44 previous studies reported no effect of GH on strength in aged individuals, consistent with our findings after GH alone. Although one epidemiologic study suggested that grip strength is greater in women taking HRT,45 most prior cohort46 or intervention47 studies are consistent with ours in finding no increases in strength in HRT users. Treatment of andropausal elderly men with higher doses of testosterone increased grip strength48 and leg strength in some49 but not other18 studies. Our observation that men treated with GH + testosterone exhibited the greatest increases in both strength and LBM is consistent with the finding that changes in strength were directly related to changes in LBM. An increase of the magnitude observed would be expected after 6 to 8 weeks of regular resistance exercise41,42 and is potentially clinically significant. However, functional significance of strength is better assessed by performance-based testing. Significant relationships of IGF-I with such measures have been reported in elderly women,50 but to date these outcomes have not been found to change in aged individuals after GH administration.30

Cardiovascular endurance capacity increased significantly only in men after GH + testosterone treatment. Our observation of a direct relationship of O2max with LBM is consistent with the interpretation that increments in O2max were partly due to increased muscle tissue and its consequent effect on oxygen consumption, rather than to enhanced cardiac output.

Participants treated with GH exhibited soft tissue adverse effects similar to those reported in acromegaly, including edema, arthralgias, and carpal tunnel symptoms. These effects were more common in men than in women, consistent with men's greater responsiveness to GH.9 Symptoms occurred more often in individuals with greater increases in IGF-I consistent with prior reports in elderly11,12,30 and middle-aged GH-deficient51 adults. We, like other authors,51 noted spontaneous reductions over time in symptoms in some affected individuals. Older age may increase susceptibility to these adverse GH effects.13 Moreover, such symptoms might presage accelerated osteoarthritis or clinically significant carpal tunnel syndrome. Coadministration of sex steroid with GH did not increase incidence of soft tissue adverse effects.

Studies of GH treatment have reported headaches in adult GH-deficient patients and benign intracranial hypertension with papilledema in children.52 We observed no increases in headaches or fundoscopic changes in GH-treated individuals. Despite a significant incidence of dependent edema, we detected no weight gain or increased blood pressure after GH administration. Treatment with GH has been associated with increases in plasma renin activity53 but not in plasma aldosterone54 or blood pressure.9 Whether aging predisposes to hormone-induced edema is unknown.

Diabetes and glucose intolerance developed significantly more often after GH treatment in men, as others have reported.11 In nonelderly GH-deficient adults, short-term GH treatment reduces insulin sensitivity, despite favorable changes in body composition,55 whereas longer-term GH therapy56 improves fasting glucose. We are unaware of analogous reports in aged adults. We found no effect of testosterone or HRT on glucose tolerance or diabetes, although testosterone replacement may improve insulin sensitivity in middle-aged men with low normal testosterone levels and obesity,57 probably by decreasing central body fat. Postmenopausal HRT exerts little effect on glucose tolerance.58

A recent study highlights concerns regarding neoplasia risk after long-term GH treatment in adults,59 possibly related to the influence of elevated IGF-I levels. Menopausal HRT is associated with small but significant increases in breast cancer risk16; estrogen use, unopposed by progestogens, increases rates of endometrial cancer.60 Whether testosterone treatment of older men stimulates prostate cancer growth is unknown. Although we observed no increase in PSA in hormone-treated men, no prospective trials, including this one, have been large enough to define risk of neoplasia for GH or testosterone replacement in elderly persons.

Using a standardized questionnaire28 we, like others,61 found no worsening of benign prostatic hyperplasia symptoms in hormone-treated men. We observed no increases in hematocrit above the normal range. Polycythemia is uncommon after testosterone replacement,62 tending to occur with high concentrations of testosterone and in men with preexisting hypoxia. About 10% of men receiving GH or GH + testosterone, but not testosterone alone, developed mild gynecomastia, consistent with prior findings.11

This study has several limitations. The number of participants, particularly women, was relatively small to determine definitively the possible positive and adverse effects. Participants were in good health relative to their age-matched peers, with potential for treatment-related "ceiling" effects on various outcomes. We did not assess performance-based outcomes and so could not determine whether changes in strength led to significant functional changes. Our study was 6 months long, which may be too short to detect temporally biphasic or other effects. We administered GH and testosterone using a nonphysiologic paradigm, and testosterone in doses lower than those used to treat hypogonadal men. Finally, we did not assess clinical outcomes during or after the study. However, this study demonstrated significant positive and adverse effects, and hence its clinical implications persist despite its limitations.

Our findings suggest that GH and sex steroid supplementation in a selected group of healthy aged women and men can exert potentially beneficial effects on body composition, and possibly improve muscle strength and cardiovascular endurance capacity in men. However, GH supplementation may lead to various adverse effects, most importantly diabetes and glucose intolerance. The beneficial effects of GH appeared to be augmented by coadministration of testosterone but not HRT. These data support the rationale for further, larger-scale investigations of the efficacy, safety, and clinical and functional utility of more physiologic hormone replacement. However, at this time, GH interventions in elderly individuals should be confined to controlled research studies.

Blackman MR, Elahi D, Harman SM. Endocrinology and aging. In: DeGroot L, ed. Endocrinology. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1995:2702-2730.
O'Connor KG, Tobin JD, Harman SM.  et al.  Serum levels of insulin-like growth factor-I are related to age and not to body composition in healthy women and men.  J Gerontol A Biol Sci Med Sci.1998;53:M176-M182.
Miller MM, Franklin KB. Theoretical basis for the benefit of postmenopausal estrogen substitution.  Exp Gerontol.1999;34:587-604.
Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men: the Baltimore Longitudinal Study of Aging.  J Clin Endocrinol Metab.2001;86:724-731.
Roy TA, Blackman MR, Harman SM, Tobin JD, Schrager M, Metter EJ. The inter-relationships of serum testosterone and free testosterone index with appendicular fat-free mass and strength in men: the Baltimore Longitudinal Study on Aging.  Am J Physiol Endocrinol Metab.2002;283:E284-E294.
Shimokata H, Andres R, Coon PJ.  et al.  Studies in the distribution of body fat, II: longitudinal effects of change in weight.  Int J Obes.1989;13:455-464.
Fried LP, Kronmal RA, Newman AB.  et al.  Risk factors for 5-year mortality in older adults: the Cardiovascular Health Study.  JAMA.1998;279:585-592.
Cefalu WT, Werbel S, Bell-Farrow AD.  et al.  Insulin resistance and fat patterning with aging: relationship to metabolic risk factors for cardiovascular disease.  Metabolism.1998;47:401-408.
Carroll PV, Christ ER, Bengtsson BA.  et al.  Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review.  J Clin Endocrinol Metab.1998;83:382-395.
Rudman D, Feller AG, Nagraj HS.  et al.  Effect of human growth hormone in men over 60 years old.  N Engl J Med.1990;323:1-6.
Cohn L, Feller AG, Draper MW, Rudman IW, Rudman D. Carpal tunnel syndrome and gynaecomastia during growth hormone treatment of elderly men with low circulating IGF-I concentrations.  Clin Endocrinol (Oxf).1993;39:417-425.
Abs R, Bengtsson BA, Hernberg-Stahl E.  et al.  GH replacement in 1034 growth hormone deficient hypopituitary adults.  Clin Endocrinol (Oxf).1999;50:703-713.
Savine R, Sonksen P. Growth hormone—hormone replacement for the somatopause?  Horm Res.2000;53:37-41.
Klatz R. Grow Young With HGH: The Amazing Medically Proven Plan to Reverse AgingNew York, NY: Harper Collins; 1997.
Haarbo J, Marslew U, Gotfredsen A, Christiansen C. Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause.  Metabolism.1991;40:1323-1326.
Writing Group for the Women's Health Initiative Investigators.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.  JAMA.2002;288:321-333.
Bhasin S, Storer TW, Berman N.  et al.  Testosterone replacement increases fat-free mass and muscle size in hypogonadal men.  J Clin Endocrinol Metab.1997;82:407-413.
Snyder PJ, Peachey H, Hannoush P.  et al.  Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age.  J Clin Endocrinol Metab.1999;84:2647-2653.
Blackman MR, Christmas C, Munzer T.  et al.  Influence of testosterone on the GH-IGF-I axis in healthy elderly men. In: Veldhuis JD, Giustina A, eds. Sex Steroid Interactions With Growth Hormone. New York, NY: Springer-Verlag; 1999:44-53.
Christmas C, O'Connor KG, Harman SM.  et al.  Growth hormone and sex steroid effects on bone metabolism and bone mineral density in healthy aged women and men.  J Gerontol A Biol Sci Med Sci.2002;57:M12-M18.
Münzer T, Harman SM, Hees P.  et al.  Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men.  J Clin Endocrinol Metab.2001;86:3604-3610.
Washburn RA, Smith KW, Jette AM, Janney CA. The Physical Activity Scale for the Elderly (PASE).  J Clin Epidemiol.1993;46:153-162.
Mazess RB, Barden HS, Bisek JP, Hanson J. Dual-energy x-ray absorptiometry for total-body and regional bone-mineral and soft-tissue composition.  Am J Clin Nutr.1990;51:1106-1112.
Lindle RS, Metter EJ, Lynch NA.  et al.  Age and gender comparisons of muscle strength in 654 women and men aged 20-93 yr.  J Appl Physiol.1997;83:1581-1587.
Frontera WR, Meredith CN, O'Reilly KP, Knuttgen HG, Evans WJ. Strength conditioning in older men.  J Appl Physiol.1988;64:1038-1044.
Bruce RA, Mazzarella JA, Jordan Jr JW, Green E. Quantitation of QRS and ST segment responses to exercise.  Am Heart J.1966;71:455-466.
 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care.1997;20:1183-1197.
Barry MJ, Fowler Jr FJ, O'Leary MP.  et al. for the Measurement Committee of the American Urological Association.  The American Urological Association symptom index for benign prostatic hyperplasia.  J Urol.1992;148:1549-1557.
Dunnett CW. Multiple comparisons procedure for computing several treatments with a control.  J Am Stat Assoc.1955;50:1096-1121.
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.
Burman P, Johansson AG, Siegbahn A, Vessby B, Karlsson FA. Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women.  J Clin Endocrinol Metab.1997;82:550-555.
Bellantoni MF, Harman SM, Cho DE, Blackman MR. Effects of progestin-opposed transdermal estrogen administration on growth hormone and insulin-like growth factor-I in postmenopausal women of different ages.  J Clin Endocrinol Metab.1991;72:172-178.
Dawson-Hughes B, Stern D, Goldman J, Reichlin S. Regulation of growth hormone and somatomedin-C secretion in postmenopausal women.  J Clin Endocrinol Metab.1986;63:424-432.
Friend KE, Hartman ML, Pezzoli SS, Clasey JL, Thorner MO. Both oral and transdermal estrogen increase growth hormone release in postmenopausal women.  J Clin Endocrinol Metab.1996;81:2250-2256.
Gentili A, Mulligan T, Godschalk M.  et al.  Unequal impact of short-term testosterone repletion on the somatotropic axis of young and older men.  J Clin Endocrinol Metab.2002;87:825-834.
O'Sullivan AJ, Crampton LJ, Freund J, Ho KK. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.  J Clin Invest.1998;102:1035-1040.
Sorensen MB, Rosenfalck AM, Hojgaard L, Ottesen B. Obesity and sarcopenia after menopause are reversed by sex hormone replacement therapy.  Obes Res.2001;9:622-626.
Tenover JS. Effects of testosterone supplementation in the aging male.  J Clin Endocrinol Metab.1992;75:1092-1098.
Hayes VY, Urban RJ, Jiang J, Marcell TJ, Helgeson K, Mauras N. Recombinant human growth hormone and recombinant human insulin-like growth factor I diminish the catabolic effects of hypogonadism in man.  J Clin Endocrinol Metab.2001;86:2211-2219.
Barbulescu K, Geserick C, Schuttke I, Schleuning WD, Haendler B. New androgen response elements in the murine pem promoter mediate selective transactivation.  Mol Endocrinol.2001;15:1803-1816.
Vitiello MV, Wilkinson CW, Merriam GR.  et al.  Successful 6-month endurance training does not alter insulin-like growth factor-I in healthy older men and women.  J Gerontol A Biol Sci Med Sci.1997;52:M149-M154.
Taaffe DR, Duret C, Wheeler S, Marcus R. Once-weekly resistance exercise improves muscle strength and neuromuscular performance in older adults.  J Am Geriatr Soc.1999;47:1208-1214.
Taaffe DR, Pruitt L, Reim J.  et al.  Effect of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men.  J Clin Endocrinol Metab.1994;79:1361-1366.
Cuttica CM, Castoldi L, Gorrini GP.  et al.  Effects of six-month administration of recombinant human growth hormone to healthy elderly subjects.  Aging (Milano).1997;9:193-197.
Cauley JA, Petrini AM, LaPorte RE.  et al.  The decline of grip strength in the menopause.  J Chronic Dis.1987;40:115-120.
Kritz-Silverstein D, Barrett-Connor E. Grip strength and bone mineral density in older women.  J Bone Miner Res.1994;9:45-51.
Dobs AS, Nguyen T, Pace C, Roberts CP. Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women.  J Clin Endocrinol Metab.2002;87:1509-1516.
Sih R, Morley JE, Kaiser FE, Perry III HM, Patrick P, Ross C. Testosterone replacement in older hypogonadal men.  J Clin Endocrinol Metab.1997;82:1661-1667.
Ferrando AA, Sheffield-Moore M, Yeckel CW.  et al.  Testosterone administration to older men improves muscle function.  Am J Physiol Endocrinol Metab.2002;282:E601-E607.
Cappola AR, Bandeen-Roche K, Wand GS, Volpato S, Fried LP. Association of IGF-I levels with muscle strength and mobility in older women.  J Clin Endocrinol Metab.2001;86:4139-4146.
Mårdh G, Lundin K, Borg G, Jonsson B, Lindeberg A. Growth hormone replacement therapy in adult hypopituitary patients with growth hormone deficiency.  Endocrinol Metab.1994;1(suppl A):43-49.
Malozowski S, Tanner LA, Wysowski D, Fleming GA. Growth hormone, insulin-like growth factor I, and benign intracranial hypertension.  N Engl J Med.1993;329:665-666.
Ho KK, O'Sullivan AJ, Hoffman DM. Metabolic actions of growth hormone in man.  Endocr J.1996;43(suppl):S57-S63.
Cuneo RC, Salomon F, Wiles CM, Hesp R, Sönksen PH. Growth hormone treatment in growth hormone-deficient adults, I.  J Appl Physiol.1991;70:688-694.
Rosenfalck AM, Fisker S, Hilsted J.  et al.  The effect of the deterioration of insulin sensitivity on beta-cell function in growth-hormone-deficient adults following 4-month growth hormone replacement therapy.  Growth Horm IGF Res.1999;9:96-105.
Johnston DG, Al-Shoumer KA, Chrisoulidou A.  et al.  Long-term effects of growth hormone therapy on intermediary metabolism and insulin sensitivity in hypopituitary adults.  J Endocrinol Invest.1999;22:37-40.
Marin P, Krotkiewski M, Bjorntorp P. Androgen treatment of middle-aged, obese men.  Eur J Med.1992;1:329-336.
Lasco A, Alvaro S, Frisina N.  et al.  Long-term transdermal estrogen therapy improves lipid profile but not insulin resistance in healthy postmenopausal women.  Diabetes Care.2000;23:422-424.
Swerdlow AJ, Higgins CD, Adlard P, Preece MA. Risk of cancer in patients treated with human pituitary growth hormone in the UK, 1959-85: a cohort study.  Lancet.2002;360:273-277.
Hulka BS, Kaufman DG, Fowler Jr WC.  et al.  Predominance of early endometrial cancers after long-term estrogen use.  JAMA.1980;244:2419-2422.
Snyder PJ, Peachey H, Berlin JA.  et al.  Effects of testosterone replacement in hypogonadal men.  J Clin Endocrinol Metab.2000;85:2670-2677.
Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males.  J Clin Endocrinol Metab.1997;82:3793-3796.

Figures

Figure 1. Flow of Patients Through the Study
Graphic Jump Location
Figure 2. Effects of 26 Weeks of Hormone or Placebo Administration
Graphic Jump Location
Effects of administration of growth hormone (GH), hormone replacement therapy, and/or placebo to women (A and C) and GH, testosterone, and/or placebo to men (B and D) 65 years or older and sequential serum levels of insulinlike growth factor I (IGF-I) (A and B), estradiol (C), and testosterone (D). Values are presented as mean (SE). To convert estradiol to pmol/L, multiply data by 3.67; to convert testosterone to nmol/L, multiply data by 0.0347. Curves were compared using repeated measures analysis of variance with P value estimates shown in the plots calculated for multiple comparisons using a post hoc Scheffé analysis. The time point (−4) before 0 weeks (baseline) represents the screening visit.
Figure 3. Bivariate Plots of the Relationships of Changes in Lean Body Mass (LBM) With Changes in Total Body Strength and O2max During 26 Weeks of Hormone or Placebo Administration
Graphic Jump Location
r and P values were calculated by linear regression for the combined groups of women and men. GH indicates growth hormone. O2max is measured as milliliters per minute per kilogram of body weight.

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics by Treatment Group*
Table Graphic Jump LocationTable 2. Effects of Treatments on Lean Body Mass and Fat Mass as Demonstrated by DXA*
Table Graphic Jump LocationTable 3. Effects of Hormone Administration on Total Body Strength*
Table Graphic Jump LocationTable 4. Effects of Hormone Treatments on Maximal Oxygen Capacity (O2max) by Graded Treadmill Exercise Testing*
Table Graphic Jump LocationTable 5. Common Adverse Effects During 26 Weeks of Treatment*
Table Graphic Jump LocationTable 6. Rates of Fasting Glucose Intolerance and Diabetes by Treatment Group*

References

Blackman MR, Elahi D, Harman SM. Endocrinology and aging. In: DeGroot L, ed. Endocrinology. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1995:2702-2730.
O'Connor KG, Tobin JD, Harman SM.  et al.  Serum levels of insulin-like growth factor-I are related to age and not to body composition in healthy women and men.  J Gerontol A Biol Sci Med Sci.1998;53:M176-M182.
Miller MM, Franklin KB. Theoretical basis for the benefit of postmenopausal estrogen substitution.  Exp Gerontol.1999;34:587-604.
Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men: the Baltimore Longitudinal Study of Aging.  J Clin Endocrinol Metab.2001;86:724-731.
Roy TA, Blackman MR, Harman SM, Tobin JD, Schrager M, Metter EJ. The inter-relationships of serum testosterone and free testosterone index with appendicular fat-free mass and strength in men: the Baltimore Longitudinal Study on Aging.  Am J Physiol Endocrinol Metab.2002;283:E284-E294.
Shimokata H, Andres R, Coon PJ.  et al.  Studies in the distribution of body fat, II: longitudinal effects of change in weight.  Int J Obes.1989;13:455-464.
Fried LP, Kronmal RA, Newman AB.  et al.  Risk factors for 5-year mortality in older adults: the Cardiovascular Health Study.  JAMA.1998;279:585-592.
Cefalu WT, Werbel S, Bell-Farrow AD.  et al.  Insulin resistance and fat patterning with aging: relationship to metabolic risk factors for cardiovascular disease.  Metabolism.1998;47:401-408.
Carroll PV, Christ ER, Bengtsson BA.  et al.  Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review.  J Clin Endocrinol Metab.1998;83:382-395.
Rudman D, Feller AG, Nagraj HS.  et al.  Effect of human growth hormone in men over 60 years old.  N Engl J Med.1990;323:1-6.
Cohn L, Feller AG, Draper MW, Rudman IW, Rudman D. Carpal tunnel syndrome and gynaecomastia during growth hormone treatment of elderly men with low circulating IGF-I concentrations.  Clin Endocrinol (Oxf).1993;39:417-425.
Abs R, Bengtsson BA, Hernberg-Stahl E.  et al.  GH replacement in 1034 growth hormone deficient hypopituitary adults.  Clin Endocrinol (Oxf).1999;50:703-713.
Savine R, Sonksen P. Growth hormone—hormone replacement for the somatopause?  Horm Res.2000;53:37-41.
Klatz R. Grow Young With HGH: The Amazing Medically Proven Plan to Reverse AgingNew York, NY: Harper Collins; 1997.
Haarbo J, Marslew U, Gotfredsen A, Christiansen C. Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause.  Metabolism.1991;40:1323-1326.
Writing Group for the Women's Health Initiative Investigators.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.  JAMA.2002;288:321-333.
Bhasin S, Storer TW, Berman N.  et al.  Testosterone replacement increases fat-free mass and muscle size in hypogonadal men.  J Clin Endocrinol Metab.1997;82:407-413.
Snyder PJ, Peachey H, Hannoush P.  et al.  Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age.  J Clin Endocrinol Metab.1999;84:2647-2653.
Blackman MR, Christmas C, Munzer T.  et al.  Influence of testosterone on the GH-IGF-I axis in healthy elderly men. In: Veldhuis JD, Giustina A, eds. Sex Steroid Interactions With Growth Hormone. New York, NY: Springer-Verlag; 1999:44-53.
Christmas C, O'Connor KG, Harman SM.  et al.  Growth hormone and sex steroid effects on bone metabolism and bone mineral density in healthy aged women and men.  J Gerontol A Biol Sci Med Sci.2002;57:M12-M18.
Münzer T, Harman SM, Hees P.  et al.  Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men.  J Clin Endocrinol Metab.2001;86:3604-3610.
Washburn RA, Smith KW, Jette AM, Janney CA. The Physical Activity Scale for the Elderly (PASE).  J Clin Epidemiol.1993;46:153-162.
Mazess RB, Barden HS, Bisek JP, Hanson J. Dual-energy x-ray absorptiometry for total-body and regional bone-mineral and soft-tissue composition.  Am J Clin Nutr.1990;51:1106-1112.
Lindle RS, Metter EJ, Lynch NA.  et al.  Age and gender comparisons of muscle strength in 654 women and men aged 20-93 yr.  J Appl Physiol.1997;83:1581-1587.
Frontera WR, Meredith CN, O'Reilly KP, Knuttgen HG, Evans WJ. Strength conditioning in older men.  J Appl Physiol.1988;64:1038-1044.
Bruce RA, Mazzarella JA, Jordan Jr JW, Green E. Quantitation of QRS and ST segment responses to exercise.  Am Heart J.1966;71:455-466.
 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care.1997;20:1183-1197.
Barry MJ, Fowler Jr FJ, O'Leary MP.  et al. for the Measurement Committee of the American Urological Association.  The American Urological Association symptom index for benign prostatic hyperplasia.  J Urol.1992;148:1549-1557.
Dunnett CW. Multiple comparisons procedure for computing several treatments with a control.  J Am Stat Assoc.1955;50:1096-1121.
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.
Burman P, Johansson AG, Siegbahn A, Vessby B, Karlsson FA. Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women.  J Clin Endocrinol Metab.1997;82:550-555.
Bellantoni MF, Harman SM, Cho DE, Blackman MR. Effects of progestin-opposed transdermal estrogen administration on growth hormone and insulin-like growth factor-I in postmenopausal women of different ages.  J Clin Endocrinol Metab.1991;72:172-178.
Dawson-Hughes B, Stern D, Goldman J, Reichlin S. Regulation of growth hormone and somatomedin-C secretion in postmenopausal women.  J Clin Endocrinol Metab.1986;63:424-432.
Friend KE, Hartman ML, Pezzoli SS, Clasey JL, Thorner MO. Both oral and transdermal estrogen increase growth hormone release in postmenopausal women.  J Clin Endocrinol Metab.1996;81:2250-2256.
Gentili A, Mulligan T, Godschalk M.  et al.  Unequal impact of short-term testosterone repletion on the somatotropic axis of young and older men.  J Clin Endocrinol Metab.2002;87:825-834.
O'Sullivan AJ, Crampton LJ, Freund J, Ho KK. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.  J Clin Invest.1998;102:1035-1040.
Sorensen MB, Rosenfalck AM, Hojgaard L, Ottesen B. Obesity and sarcopenia after menopause are reversed by sex hormone replacement therapy.  Obes Res.2001;9:622-626.
Tenover JS. Effects of testosterone supplementation in the aging male.  J Clin Endocrinol Metab.1992;75:1092-1098.
Hayes VY, Urban RJ, Jiang J, Marcell TJ, Helgeson K, Mauras N. Recombinant human growth hormone and recombinant human insulin-like growth factor I diminish the catabolic effects of hypogonadism in man.  J Clin Endocrinol Metab.2001;86:2211-2219.
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