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Am J Physiol Endocrinol Metab 290: E1006-E1013, 2006. First published January 3, 2006; doi:10.1152/ajpendo.00166.2005
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Effects of GH and/or sex steroids on circulating IGF-I and IGFBPs in healthy, aged women and men

Thomas Münzer, Clifford J. Rosen, S.Mitchell Harman, Katherine M. Pabst, Carol St. Clair, John D. Sorkin, and Marc R. Blackman

Endocrine and Metabolism Sections, Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health; Division of Endocrinology and Metabolism, Departments of Medicine, Johns Hopkins Bayview Medical Center and Johns Hopkins University School of Medicine, Baltimore, Maryland; and the Maine Center for Osteoporosis and Education, St. Joseph's Hospital, Bangor, Maine

Submitted 15 April 2005 ; accepted in final form 22 December 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Circulating GH, IGF-I, IGFBP-3, and sex steroid concentrations decrease with age. GH or sex steroid treatment increases IGFBP-3, but little is known regarding the effects of these hormones on other IGFBPs. We assessed the effects of 26 wk of administration of GH, sex steroids, or GH + sex steroids on AM levels of IGF-I, IGFBPs 1–5, insulin, glucose, and osteocalcin and 2-h urinary excretion of deoxypyridinolline (DPD) cross-links in 53 women and 71 men aged 65–88 yr. Before treatment, in women and men, IGF-I was directly related to IGFBP-3 (P < 0.001 and P < 0.0001) and IGFBP-1 to IGFBP-2 (P = 0.0001). In women, IGFBP-1 was inversely related to insulin (P < 0.0005) and glucose (P < 0.005) and IGFBP-4 to osteocalcin (P < 0.01). IGFBP-4 and IGFBP-5 were not significantly related to DPD cross-links. GH and/or sex steroid increased IGF-I levels in both sexes, with higher concentrations in men (P < 0.001). In women, the IGF-I increment after GH was attenuated by hormone replacement therapy (HRT) coadministration (P < 0.05). Hormone administration also increased IGFBP-3. IGFBP-1 was unaffected by GH + sex steroids, whereas GH decreased IGFBP-2 by 15% in men (P < 0.05). Hormone administration did not change IGFBP-4, whereas in men IGFBP-5 increased by 20% after GH (P < 0.05) and 56% after GH + testosterone (P = 0.0003). These data demonstrate sexually dimorphic IGFBP responses to GH. Additonally, HRT attenuated or prevented GH-mediated increases in IGF-I and IGFBP-3. Whether GH and/or sex steroid administration alters local tissue production of IGFBPs and whether the latter influence autocrine or paracrine actions of IGF-I remain to be determined.

growth hormone; insulin-like growth factor-binding protein

INSULIN-LIKE GROWTH FACTOR-BINDING PROTEINS (IGFBPs) are members of a structurally and genetically related superfamily of proteins that bind to insulin-like growth factors (IGFs) with high, but variable, affinities (34). In addition to their principal roles as modulators of endocrine, paracrine, and autocrine actions of IGFs, IGFBPs exert growth hormone (GH)-independent effects on various tissues in vivo and in vitro (38, 59). The detailed mechanisms of IGFBP synthesis and their metabolic activities remain incompletely understood. However, it has been reported (6, 64, 65) that circulating levels of IGFBP-1 are regulated by insulin and IGF-I. IGFBP-2 is also related to insulin levels (13), whereas increases in IGFBP-3 are closely correlated with those in IGF-I in response to GH in children (47) and adults (39) with GH deficiency (GHD). IGFBP-4 and -5 inhibit and stimulate, respectively, IGF-mediated effects on bone (53). How these important modulatory proteins are affected by aging and age-related changes in endocrine balance and the extent to which hormone replacement reverses such changes is incompletely understood.

Normal aging is associated with declines in GH secretion and IGF-I levels (14) as well as with decreases in circulating sex steroids in both women and men (29, 45, 49). The age-related decline in IGF-I levels has been attributed in part to a 192-bp polymorphism in the IGF-I gene (61). In addition, aging is associated with increases in serum levels of IGFBP-1, -2, and -4 (9, 33, 55, 63) and decreased serum levels of IGFBP-3 and -5 (35, 52, 60). Several studies (3, 18, 32, 40, 68) in healthy, aged women and men and in adult patients with GHD have reported significant and dose-dependent increases in serum levels of IGFBP-3 after GH administration. In addition, GH administration has been reported to increase IGFBP-4 and -5 levels in aged patients with GHD (20) and IGFBP-1 levels in healthy, nonelderly individuals (27). Coadministration of testosterone (T) and GH in eight young GH-deficient men, however, decreased IGFBP-3 levels and increased IGFBP-1 (21). To date, little is known about the effects of sex steroids on circulating IGFBPs. In men, higher circulating T predicts higher levels of IGF-I, and greater lean body mass (LBM) is associated with greater concentrations of IGFBP-3 (76). T administration to older men increased intramuscular mRNA concentrations of IGF-I and decreased mRNA expression of IGFBP-4 (71), suggesting tissue-specific T-induced effects on local expression of IGFBPs. In contrast, oral estrogen has been found to increase IGFBP-1 levels in postmenopausal women in some studies (42, 56) but lower IGF-I and IGFBP-3 levels in another report (76).

In the present study, we explored the hypothesis that the known relationships of IGFBPs with GH, IGF-I, sex steroids, and measurement of glucose and bone metabolism in healthy young adults are maintained in aged individuals. Therefore, we examined the separate and interactive effects of 6 mo of GH and/or sex steroid administration on serum levels of IGF-I and IGFBPs 1–5, as well as selected metabolic and bone biomarkers, in a group of healthy, ambulatory, community-dwelling women and men over 65 yr of age.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Study Population

Participants were recruited by mailed brochures and newspaper advertisements. All were 65 yr of age or older and healthy by history, physical examination, routine serum chemistries, urinalysis, and graded treadmill electrocardiogram testing. Subjects were nonsmoking, drank no more than 30 g of alcohol/day, and took no medications known to interfere with GH/IGF-I axis activity or gonadal steroid levels. Women were postmenopausal and had taken no hormone replacement therapy (HRT) for at least 3 mo before the study. Eighteen women reported having taken HRT previously. Among women in all treatment groups combined, the mean period of discontinuation of HRT before study participation was 12 ± 3 yr. Four of the 18 women were actively taking HRT until 3 mo before randomization to receive either placebo + placebo (n = 2) or HRT + placebo (n = 2). No man was taking T replacement before entry into the study. Eligible women and men were also selected to have age-related reductions (≥1 SD below the mean for values in healthy adults aged 20–35 yr) of their circulating IGF-I levels (230 µg/l) and, for men, of their serum T (16.3 nmol/l). The study protocol was approved by the combined Institutional Review Board of the Johns Hopkins Bayview Medical Center and the Intramural Research Program, National Institute on Aging (NIA). Written informed consent was obtained from each participant.

Study Protocol

The study was conducted as a randomized, double-masked, double-dummy, placebo-controlled, noncrossover clinical trial using a 2 x 2 factorial design for a total period of 26 wk. Thus all participants received active or placebo GH and active or placebo sex steroid, and each active hormone was given alone and in combination with the other. Recombinant human GH (Nutropin; Genentech) was administered as 20 µg/kg body wt, self-injected subcutaneously 3 times/wk in the evening. HRT was given as a 100-µg/day estradiol patch (Estraderm; Novartis), plus 2.5 mg of medroxyprogesterone acetate (Provera; Pharmacia & Upjohn) for the first 10 days of each month, and T was administered as intramuscular injections of 100 mg of T enanthate (Delatestryl Injection; Bio-Technology General) every 2 wk.

At baseline, participants were admitted on the evening before study to the General Clinical Research Center at the Johns Hopkins Bayview Medical Center, where they received a standard dinner. The next morning, after an overnight fast, blood samples were obtained for baseline determinations of serum estradiol (E2) in women or T in men and IGF-I, IGFBPs, insulin, glucose, and osteocalcin. Urine was collected for determinations of 24-h excretion of urinary creatinine and deoxypyridinolline (DPD) cross-links. Subjects were subsequently seen on a weekly basis as outpatients for clinical assessments of possible adverse effects; every 4 wk, blood was collected for serial assessments of serum IGF-I, T, and E2. T levels were measured 7 days after the intramuscular T injections. Medication doses were reduced by the study safety monitor on the basis of clinical symptoms and/or elevations of serum levels of IGF-I >350 µg/l, T >28 nmol/l, or E2 >55 pmol/l. For each reduction of an active medication, a corresponding reduction was carried out in the corresponding placebo to maintain blinding. Measurements of IGFBPs and biomarkers of metabolic and bone function were assessed at baseline and at week 26.

Study participants were advised to consume their customary diets and maintain their usual level of physical activity during the 26-wk protocol. Three-day diet histories were obtained by a nutritionist, and physical activity patterns were assessed using the Physical Activity Scale for the Elderly (PASE) (75) at baseline and at week 26.

Hormone Assays

IGF-I. Total serum IGF-I levels were measured by RIA after acid-ethanol extraction (Endocrine Sciences Laboratories, Calabasas Hills, CA). Sensitivity of the IGF-I assay was 30 µg/l, and the intra- and interassay coefficients of variation (CVs) were, respectively, 5.9 and 7.3% at 289 µg/l and 4.6 and 6.3% at 591 µg/l.

IGFBPs. IGFBP-1 and IGFBP-2 levels were measured by immunoradiometric assay (IRMA) and RIA, respectively (Diagnostic Systems Laboratories, Webster, TX). The sensitivity of the IGFBP-1 assay was 0.33 ng/ml, and the intra-assay CVs were 4.2% at 5.2 ng/ml, 4.6% at 50.2 ng/ml, and 2.7% at 144.6 ng/ml. For IGFBP-1, intra- and interassay CVs were 2.5 and 9.4%, respectively. The sensitivity of the IGFBP-2 assay was 0.5 ng/ml with CVs of 8.5% at 13 ng/ml, 6.2% at 32.2 ng/ml, and 4.7% at 94.4 ng/ml. The intra- and interassay CVs were 7.8 and 17.1%, respectively. IGFBP-3 was measured by RIA (Endocrine Sciences Laboratories). The IGFBP-3 assay intra- and interassay CVs were 2.7 and 7.5%, respectively. Serum IGFBP-4 levels were determined by RIA using recombinant human IGFBP-4 as tracer and standard and antibodies against human recombinant IGFBP-4 raised in guinea pigs as described (33). Serum IGFBP-5 levels were determined by RIA using recombinant human IGFBP-5 as tracer and standard and antibodies against human recombinant IGFBP-5 raised in guinea pigs, as described (52). Serum samples were diluted 1:10 in RIA buffer before assay. In this assay, the range of measurement was between 7.8 and 125 ng/ml and the half-maximal effective dose was 27 ng/ml. The intra- and interassay CV was <8%. There is no cross-reactivity with other IGFBPs.

Sex steroids. Serum levels of E2 and T were determined by RIA (Coat-A-Count; Diagnostic Products, Los Angeles, CA) performed in the laboratory of the Endocrine Section, NIA. This type of T assay has recently been validated in a comparison study with isotope dilution gas chromatography-mass spectrometry (67). For E2, the minimum detectable concentration was 7.3 pmol/l, and the interassay CVs were 7.6% at 32 pmol/l, 5.0% at 68 pmol/l, and 5.7% at 182 pmol/l, and the intra-assay CVs were 9.7% at 31 pmol/l, 9.3% at 66 pmol/l, and 4.3% at 185 pmol/l. For T, minimum detectible concentration was 0.3 nmol/l, and the interassay CVs were 5.9% at 2.6 nmol/l, 3.9% at 10.4 nmol/l, 3.2% at 24.5 nmol/l, and 4.8% at 36.1 nmol/l, and intra-assay CVs were 11.2% at 2.1 nmol/l, 6.7% at 10.4 nmol/l, 1.5% at 20.7 nmol/l, and 3.1% at 34.6 nmol/l.

Insulin and glucose. Serum insulin levels were determined by RIA (Linco Research, St. Louis, MO). This assay has a sensitivity of 1.2 pM with a linear range from 1.2 to 120 pM. Intra-assay and interassay CVs were 2.1 and 2.8%, respectively. Serum glucose was measured using an automated glucose oxidase method (Beckman Diagnostics, Fullerton, CA) with an intra-assay CV of 2.8% and an interassay CV of 2.1%.

Markers of Bone Formation and Turnover

Serum osteocalcin was measured by IRMA (Nichols Institute Diagnostics, San Juan Capistrano, CA) using two sets of goat antibodies directed against human osteocalcin, one labeled in solution and the other immobilized on coated beads, with a sensitivity of 0.06 ng/ml, an intra-assay CV of 3.0%, and an interassay CV of 6.7%. Urinary excretion of DPD cross-links was quantified after a 2-h sampling period by ELISA (Metra Biosystems, Palo Alto, CA) with a sensitivity of 1 nM, an intra-assay CV of 8.2%, and an interassay CV of 7.9%. Urinary creatinine excretion was determined on a 24-h collection specimen by an automated method (Beckman Instruments) with a linear range of 0.04 to 0.11 mmol, an intra-assay CV of 1.1%, and an interassay CV of 1.6%. The ratio of creatinine to DPD cross-links (creatinine DPD) was used to estimate bone turnover.

Statistical Analyses

All data are expressed as means ± SE. Data were analyzed using SAS version 6.12 (SAS Institute, Cary, NC). Skewness of data was tested by visual inspection of Q-Q plots, stem and leaf plots, and box plots. Because data for serum insulin levels were skewed to the right of normal distribution, we analyzed log-transformed values. Possible sex differences in baseline measures between groups were assessed by the unpaired Student’s t-test. Differences between active treatment group and placebo group in continuous variables at baseline and after 26 wk were assessed by analysis of covariance, using the General Linear Models (GLM) procedure to control for unequal group size. The dependent variable in the analyses was the change (post-pre) value of the outcome variable. Independent variables included the subject's age, the initial value of the outcome variable, and a variable indicating treatment group (GH + sex steroid, GH alone, sex steroid alone, neither GH nor sex steroid). All post hoc comparisons of the three treatment groups to double placebo were adjusted for multiple comparisons using Dunnett's test. Significance was set at a two-tailed P ≤ 0.05.

Two women randomized to receive GH and GH with or without HRT and one man randomized to receive GH exhibited baseline serum levels of IGFBP-1 that were more than 3 SD beyond mean serum levels compared with those of other individuals in the same group. Elimination of data from these participants did not significantly alter the results of the GLM analysis. The results reported here include all data for IGFBP-1. None of the other measured variables in these three study participants were outliers. We also performed univariate regression analyses to assess relationships of IGFBPs with metabolic and bone biomarkers, separately in women and men, both at baseline and after hormone intervention.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
We studied 124 healthy elderly women (n = 53) and men (n = 71), mean age 71 ± 0.4 yr (range 65–88 yr). At baseline, men were heavier than women. During the 26 wk of hormone administration, weight did not change significantly in any of the intervention groups (data not shown). Table 1 summarizes baseline weights and serum levels of IGF-I and IGFBP-3 at baseline and after 6 mo of hormone intervention. As reported previously (8), there were no significant group differences in the numbers of women or men with weight changes >3 kg or changes in mean body weight in any treatment group; 3-day diet histories and PASE scores did not differ before or after treatment in either sex (data not shown).


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  		Table 1. Baseline body weight and serum levels of IGF-I and IGFBP-3 at baseline and after 26 wk of hormone administration in healthy, aged women and men

 
Interrelationships of IGF-I, IGFBPs, Age, and Metabolic Markers

Within the relatively narrow age range of subjects studied, there were no significant baseline relationships of IGF-I or any of the IGFBPs with age in women or men evaluated separately or together (data not shown).

At baseline, IGF-I and IGFBP-3 were directly related to one another in the combined treatment groups of women (r = 0.45, P = 0.0006) and men (r = 0.61, P < 0.0001). Moreover, the change after treatment (all treatment groups combined) in serum IGFBP-3 levels was directly related to the change in IGF-I levels in women (r = 0.43, P = 0.0007) and men (r = 0.43, P = 0.0001). Baseline serum levels of IGF-I did not significantly predict changes in any of the IGFBPs in either sex, nor did baseline total T levels predict changes in IGFBPs in men (data not shown).

At baseline, IGFBP-1 and IGFBP-2 levels were directly related in women (r = 0.68, P = 0.0001) and men (r = 0.47, P = 0.0001). Posttreatment changes in IGFBP-1 were directly related to changes in IGFBP-2 in men (r = 0.52, P = 0.0001), but not in women. There were no significant relationships between IGFBP-4 and IGFBP-5 levels in either sex at baseline or in response to treatment.

At baseline, IGFBP-1 was inversely related to fasting levels of insulin (r = –0.48, P = 0.0004) and glucose (r = –0.39, P < 0.004) in women, but not in men. The changes in serum IGFBP-1 levels were not significantly related to the observed changes in insulin levels in either sex.

At baseline, IGFBP-2 was inversely related to insulin in women (r = –0.43, P < 0.005) and men (r = –0.38, P < 0.005). Similarly, IGFBP-2 was inversely related to fasting glucose in women (r = –0.35, P = 0.01) and men (r = –0.35, P = 0.003). The change in IGFBP-2 was not significantly related to changes in insulin or fasting glucose in either sex.

At baseline, IGFBP-4 levels were inversely related to serum osteocalcin levels in women (r = –0.35, P = 0.0054), but not in men. There were no significant baseline relationships of IGFBP-4 with urinary DPD cross-links excretion, or IGFBP-5 with osteocalcin or urinary DPD cross-links excretion, in either sex. The changes in IGFBP-4 and -5 were not significantly related to changes in the measured bone markers in either sex (data not shown).

Effects of Sex Steroid Replacement on Serum E2 and T levels

In women, administration of HRT or GH + HRT increased serum E2 levels similarly, from ≤7.3 to 31 ± 5.5 (P = 0.005) and 34 ± 5.1 pmol/l (P = 0.0001), respectively. In men, T alone increased serum total T levels from 15.3 ± 0.8 to 20.2 ± 1.6 nmol/l (P = 0.005), and GH + T increased T levels from 14.6 ± 1.2 to 18.1 ± 0.9 nmol/l (P = 0.0005) with no difference in either sex between the sex steroid treatment groups with and without GH. Neither placebo nor GH treatment significantly changed sex steroid levels in women or men (data not shown).

Hormone Effects on Serum Levels of IGF-I and IGFBP-3

At baseline, serum IGF-I levels were higher in men vs. women but did not differ significantly among subgroups in either sex (Table 1). In women randomized to receive GH and GH + HRT, IGF-I levels rose significantly (P < 0.05), with a significantly lesser response to GH in women receiving GH + HRT compared with GH alone (P < 0.05). In men, administration of GH alone or GH + T increased IGF-I levels, with no difference in response between these treatment groups. Neither placebo nor sex steroid treatment significantly affected IGF-I levels in women or men. After 26 wk of GH administration, IGF-I levels were higher in men vs. women (P = 0.01). In women, serum IGFBP-3 levels increased significantly after GH (39%) but not after GH + HRT (6%). In men, IGFBP-3 increased similarly after both GH (27%) and GH + T (35%).

Hormone Effects on Serum IGFBP-2, -4, and -5

At baseline, serum levels of IGFBP-1, -2, -4, and -5 did not differ significantly among treatment groups or between the sexes (Tables 2 and 3). There were no significant changes in IGFBP-1 levels in any treatment group of women or men (data not shown) or of IGFBP-2 levels in women. In contrast, in men, IGFBP-2 levels decreased by 15% after GH but remained unchanged after GH + T (Table 2). There were no significant effects of any intervention on serum IGFBP-4 levels in either women or men or of IGFBP-5 levels in women (Table 3). In contrast, IGFBP-5 levels increased in men after GH (20%) and GH + T (56%).


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  		Table 2. Levels of IGFBP-1 and -2, IRI, and FBG at baseline and after 26 wk of hormone administration in healthy, aged women and men

 

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  		Table 3. Serum levels of IGFBP-4 and -5, urinary DPD and serum OC at baseline and after 26 wk of hormone administration in healthy, aged women and men

 
Hormone Effects on Fasting Insulin and Glucose Levels and on Biochemical Markers of Bone Metabolism

In women, GH alone increased fasting insulin levels by 112% and fasting glucose by 4.5%, whereas there were no significant effects of HRT on either measure (Table 2). The addition of HRT to GH appeared to eliminate the GH effect on fasting insulin and glucose levels. In men, GH + T, but not GH or T alone, increased fasting insulin by 30%, whereas fasting glucose levels increased by 11% after GH alone but not after T or GH + T.

In women, GH increased serum osteocalcin levels and urinary excretion of DPD cross-links, whereas HRT and GH + HRT did not significantly change osteocalcin or DPD cross-links (Table 3). The addition of HRT to GH appeared to eliminate the GH effects on osteocalcin and urinary DPD cross-links. In men, GH and GH + T increased osteocalcin similarly, whereas T alone exerted no effects on markers of bone turnover. Urinary DPD cross-links did not change significantly in any treatment group.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In studies of healthy, community-dwelling men and women, concentrations of IGF-I, IGF-II, and IGFBP-3 decreased with age (25, 60). In elderly men, serum IGFBP-1 levels were positively related to age and inversely correlated with insulin, insulin resistance, obesity, and IGF-I (77). Also in men, higher serum IGFBP-2 concentrations have been related to heightened disability, lower physical performance scores, and reduced muscle strength and bone mineral density (BMD) (72). Moreover, IGFBP-2 appears to be a negative predictor of BMD among men and women, particularly postmenopausal women (1). Thus IGFBPs may be markers for, or may be directly involved in, processes leading to age-related disease and disability (diabetes, osteoporosis, sarcopenia). The relationships of age-related changes in these binding proteins to changes in sex steroid hormones and GH is an area of active investigation.

In the present study, we investigated the effects of 26 wk of GH and/or sex steroid administration on circulating levels of IGF-I and IGFBPs 1–5 and glucose, insulin, and bone biochemical markers in a cohort of healthy, community-dwelling, ambulatory, older women and men. We (8) have previously reported effects of hormone intervention on body composition, muscle strength, and cardiovascular endurance in this same cohort. We (8) and others (32, 62) have described that GH administration increases serum levels of IGF-I in older men and women. Moreover, GH administration increases IGF-I to a greater extent in men than in women, as has been reported in both the elderly (8) and nonelderly GH-deficient adults (11, 37). Sexually dimorphic responses of circulating IGF-I to GH are thought to result, in part, from sex-related differences in body composition, sex steroids, and GH-binding proteins (37).

As we previously reported (8), in women, transdermal estrogen administration did not significantly affect IGF-I levels, a finding consistent with prior reports (4, 31) that doses of transdermal estrogens similar to or lower than those we employed do not alter IGF-I levels. Our finding that, in elderly, somatopausal women, coadministration of HRT + GH attenuated the GH effect on serum IGF-I levels is consistent with prior results showing that orally administered estrogens decrease circulating IGF-I (17, 22) and hepatic IGF-I mRNA expression (10, 27), as well as the IGF-I response to GH in middle-aged women (36). Thus an interaction between dose and duration of estrogen exposure probably influences the GH-mediated hepatic IGF-I response. In contrast, at the hypothalamic-pituitary axis, stimulation of GH release with GH-releasing peptide in the presence of estrogens enhances GH secretory response in postmenopausal women (2). Significant positive correlations between serum T levels and spontaneous GH secretion (74) and GHRH-stimulated GH release have been reported in some (16), but not other (12), studies of older andropausal men. In a cross-sectional survey of healthy aging men, we recently reported (7) that age was a strong, independent predictor of serum IGF-I and IGFBP-3 levels and that levels of total T were related to IGF-I independently of age. Thus it could be hypothesized that the age-related decline in T secretion in healthy men contributes to the concomitant physiological reduction in GH secretion with age and that the latter is reversed, at least in part, by T administration. Our finding that serum IGF-I levels were unaffected by 6 mo of T administration to healthy older men and increased similarly after administration of combined GH + T and GH alone (8), coupled with the observation that hepatic IGF-I gene expression in young male rats is similar after administration of GH and GH + T (58), does not support this hypothesis. However, in a short-term study (23), neither low (100 mg) nor high (200 mg) doses of T augmented GH secretion in eugonadal young men, but the higher dose significantly amplified 24-h basal rhythmic GH production and elevated serum IGF-I concentrations in older men. In another study (21), intramuscular injections of 250 mg of T in younger male GH-deficient patients, in addition to ongoing GH therapy, decreased IGF-I and IGFBP-3 levels. These studies suggest that dose and state of hormone repletion vs. hormone deficiency may mediate different effects of T on the synthesis of IGF-I and IGFBPs.

GH increased IGFBP-3 levels in our women, but these effects were blunted after coadministration of HRT. A previous study (54) reporting that HRT attenuates hepatic IGFBP-3 gene expression is consistent with the present findings. In comparison, in men, IGFBP-3 levels increased similarly after GH and GH + T, which is consistent with a report in GH-deficient lit/lit mice wherein combined IGF-I and T treatment and IGF-I led to similar increases in IGFBP-3 (19). Our finding of strong direct relationships of IGF-I with IGFBP-3 before and after hormone/placebo treatment confirms previous observations in GH-deficient adults (39) and in aged women (32) and men (15). Moreover, the observation that IGFBP-3 increased after GH treatment in older women and men is consistent with our hypothesis that the decrease in GH with age is partly responsible for the age-related decline in IGFBP levels.

We observed that 6 mo of transdermal estrogen alone did not affect IGFBP-3 levels. The present finding contrasts with our prior observation that IGFBP-3 levels decreased after 6 wk of similar doses of transdermal estrogens (5) but is consistent with the report of unchanged IGFBP-3 levels after 12 wk of transdermal estrogen replacement therapy given to younger postmenopausal women (41). Taken together, these findings suggest that the duration of transdermal estrogen use, independent of dose, influences IGFBP-3 levels in postmenopausal women. T administration alone also did not alter serum IGFBP-3 levels in our aged men, whereas T administration has been shown to decrease IGFBP-3 levels in hypopituitary nonelderly men (21). At baseline, IGFBP-1 was inversely related to insulin in women, but not in men. IGFBP-1 and insulin have been reported to be inversely related in one study of young and old men (6), but not in another investigation of aged women and men (63). The reasons for these apparent discrepancies are not clear. It has been speculated that the increase of IGFBP-1 with age is partly determined by the decline in IGF-I and that insulin and glucose remain important regulators of circulating IGFBP-1 even in advanced age (6).

Short-term administration of GH has been reported to decrease IGFBP-1 levels in postmenopausal women (43) and GH-deficient adults (24); in the latter patients, insulin levels increased. Recent data suggest a direct GH-mediated downregulation of hepatic IGFBP-1 gene transcription as a possible mechanism (46). In contrast, GH infusion produced transient increases in IGFBP-1 levels in healthy young adults (27). In the present study, administration of GH did not affect circulating IGFBP-1, as previously reported (24) in elderly GH-deficient patients treated with GH for 3 mo. Serum insulin and glucose levels increased after GH in women and after GH + T in men. The finding that transdermal estrogens in our women did not influence IGFBP-1 levels, whereas oral estrogens have been reported to increase IGFBP-1 levels (42, 56), suggests that the route of estrogen administration in menopausal women affects IGFBP-1 independently of the presence or absence of GH.

At baseline, IGFBP-2 levels were inversely related to those of insulin in women and men. In a prior study (13), levels of IGFBP-2, unlike those of IGFBP-1, did not decrease after insulin infusion or endogenous insulin increases induced by food intake. IGFBP-2 decreased after administration of GH to our men, but not to women, and were unaffected by sex steroids. Short-term administration of GH has been reported to decrease circulating IGFBP-2 in postmenopausal women and in GH-deficient adults (24, 43), whereas long-term GH administration exerted no effect on IGFBP-2 levels in the latter patients (24). Our observation of an apparent sexually dimorphic effect of GH on IGFBP-2 levels may be explained in part by the lesser GH-induced fluctuations in insulin and glucose levels in our men vs. women and/or by other as yet unknown factors.

We found that serum levels of IGFBP-4 did not change significantly after hormone intervention in women or men. In contrast, in men, IGFBP-5 increased similarly after GH and GH + T. Prior studies (69) in GH-deficient adults revealed an initial increase in IGFBP-4 and -5 levels after GH administration followed by a later return in IGFBP-4 levels to normal. Similar temporally biphasic responses of IGFBP-4 have been reported after administration of GH to postmenopausal women (43) and of MK-677, an oral GH secretagogue, to young healthy obese men (66).

Several laboratory-based studies suggest that IGFBP-4 inhibits (51, 78) and IGFBP-5 stimulates (53) IGF-induced effects on bone. In addition, IGF-I-independent effects of IGFBP-5 on bone formation have been observed in an IGF-I knockout mouse model (50). Moreover, estrogens increase IGFBP-4 secretion in the human osteoblast (44), whereas T stimulates osteoblastic IGF-I mRNA expression and chondrocyte production of IGF-I and the IGF-I receptor (26, 48). In cortical bone matrix from osteoporotic women, age-related increases in IGFBP-3, IGFBP-5, and osteoprogerin are inversely correlated with femoral neck and lumbar spine BMD (70). Our finding of a significant inverse relationship of IGFBP-4 and osteocalcin levels in women is compatible with the above observations. Whether in vivo administration of GH and/or sex steroids alters local bone or chondrocyte production of IGFBP-4 and IGFBP-5 and whether the latter influence autocrine or paracrine actions of IGF-I remain to be determined.

Our study has several limitations. First, the GH doses and application regimens in our protocol were chosen on the basis of study designs from earlier long-term GH intervention trials in aged persons (57, 62) and studies applying different GH dose regimens using a short-term protocol (43). The GH dose employed, when averaged on a weekly basis, is typical of those reported in multiple studies (28) of adult GH-deficient patients and ranged from 9 to 10 µg·kg–1·day–1 when calculated for individual subjects. More recent reports (28) have stressed that lower incidents of adverse effects are observed when doses are reduced to 3–6 µg·kg–1·day–1, but beneficial effects on LBM and fat mass may also be diminished at these lower GH doses, especially in older patients. Second, we assessed outcome data only at baseline and 26 wk; consequently, we might have missed earlier GH-induced changes in IGFBP levels. Third, the use of medroxyprogesterone acetate (MPA), a progestin with moderate androgenic activity, may have altered serum levels of some IGFBPs. Heald et al. (30) reported that the addition of MPA to oral conjugated estrogens blunted estrogen-mediated responses in serum levels of these binding proteins. In contrast, IGFBP-2 levels increased after estrogens with and without MPA, whereas levels of IGFBP-4 were unchanged. Whether MPA-associated androgen effects in postmenopausal women blunt IGF-1-induced feedback loops in a manner similar to that reported by Veldhuis et al. (73) in older men remains to be determined.

Further studies appear warranted to assess the effects of GH and sex steroid treatment on IGFBPs, and the possible relationships of IGFBPs with carbohydrate metabolism and indicators of fracture risk, in diverse populations of older women and men.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported in part by National Institute on Aging (NIA) Grant RO-1 AG-11005 (to M. R. Blackman); General Clinical Research Center Grant MO-1-RR-02719 from the National Center for Research Resources, Bethesda, MD; the Intramural Research Programs, NIA, Baltimore, MD and NCCAM, Bethesda, MD; and KO-1 Grant AG-01054-01A1 (to J. D. Sorkin) at the University of Maryland School of Medicine and Baltimore Veterans Affairs Geriatric Research, Education and Clinical Center, Baltimore, MD. T. Münzer was supported by the Fogarty International Fellowship Program of the National Institutes of Health.


   ACKNOWLEDGMENTS
 
We gratefully acknowledge the expert assistance of Drs. Michele Bellantoni, Colleen Christmas, and Jimmy Edmond and the nursing staff of the Johns Hopkins Bayview Medical Center's General Clinical Research Center; Genentech and Novartis Pharmaceuticals for their generous provisions, respectively, of recombinant human GH and transdermal estradiol; Dr. S. Mohan for constructive comments and performance of the IGFBP-4 and IGFBP-5 assays; and Drs. Michel Bernier and Neal Fedarko for their helpful critical reviews of this manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. R. Blackman, Endocrine Section, Laboratory of Clinical Investigation, National Center for Complementary and Alternative Medicine, 9 Memorial Drive, Rm. 1N-119, National Institutes of Health, Bethesda, MD 20892 (email: blackmam{at}mail.nih.gov)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
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