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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1314
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2941-2947
Copyright © 2005 by The Endocrine Society

Testosterone and Estradiol Regulate Free Insulin-Like Growth Factor I (IGF-I), IGF Binding Protein 1 (IGFBP-1), and Dimeric IGF-I/IGFBP-1 Concentrations

Johannes D. Veldhuis, Jan Frystyk, Ali Iranmanesh and Hans Ørskov

Division of Endocrinology and Metabolism (J.D.V.), Department of Internal Medicine, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Medical Research Laboratories (J.F., H.Ø.), University Hospital, DK-8000 Aarhus, Denmark; and Endocrine Service (A.I.), Medical Section, Salem Veterans Affairs Medical Center, Salem, Virginia 24153

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The present study tests the clinical postulate that elevated testosterone (Te) and estradiol (E2) concentrations modulate the effects of constant iv infusion of saline vs. recombinant human IGF-I on free IGF-I, IGF binding protein (IGFBP)-1, and dimeric IGF-I/IGFBP-1 concentrations in healthy aging adults. To this end, comparisons were made after administration of placebo (Pl) vs. Te in eight older men (aged 61 ± 4 yr) and after Pl vs. E2 in eight postmenopausal women (62 ± 3 yr). In the saline session, E2 lowered and Te increased total IGF-I; E2 specifically elevated IGFBP-1 by 1.5-fold and suppressed free IGF-I by 34%; and E2 increased binary IGF-I/IGFBP-1 by 5-fold more than Te. During IGF-I infusion, the following were found: 1) total and free IGF-I rose 1.4- to 2.0-fold (Pl) and 2.1–2.5-fold (Te) more rapidly in men than women; 2) binary IGF-I/IGFBP-1 increased 3.4-fold more rapidly in men (Te) than women (E2); and 3) end-infusion free IGF-I was 1.6-fold higher in men than women. In summary, E2, compared with Te supplementation, lowers concentrations of total and ultrafiltratably free IGF-I and elevates those of IGFBP-1 and binary IGF-I/IGFBP-1, thus putatively limiting IGF-I bioavailability. If free IGF-I mediates certain biological actions, then exogenous Te and E2 may modulate the tissue effects of total IGF-I concentrations unequally.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONCENTRATIONS OF TOTAL IGF-I and sex steroid hormones fall pari passu in aging adults, thereby putatively contributing to relative frailty (1, 2, 3, 4, 5, 6). Both testosterone (Te) and estradiol (E2) stimulate GH secretion, but only Te consistently elevates total IGF-I concentrations (7, 8, 9, 10, 11, 12, 13, 14, 15, 16). This mechanistic distinction reflects in part the capability of estrogenic steroids to inhibit the hepatic actions of GH (17). On the other hand, relative IGF-I depletion in aging individuals is due primarily to reduced GH secretion, inasmuch as small doses of recombinant human (rh) GH elevate IGF-I concentrations by comparable increments in older and young adults (18, 19).

Although free IGF-I concentrations also decrease dramatically in healthy older individuals (20, 21), how concomitant deficiency of sex steroids modifies free IGF-I availability is not known (22, 23, 24). Physiological regulation of free IGF-I concentrations is important, in that the unbound peptide appears to mediate certain biological effects of this trophic hormone (25). For example, in experimental animals, free IGF-I concentrations correlate positively with somatic growth, cellular replication, glucose disposal, and neuronal viability (26, 27, 28, 29).

IGF-I associates with six major binding proteins in plasma (30). Among these, IGF binding protein (IGFBP)-3 and IGFBP-1 control free IGF-I concentrations in a sustained (hours) and rapid (minutes) fashion, respectively. Administration of E2 or Te does not alter IGFBP-3 concentrations in short-term (several weeks long) clinical experiments, whereas E2 (but not Te) elevates IGFBP-1 concentrations (16, 31, 32). In view of such data, we reasoned that E2 and/or aromatized Te might enhance formation of the stable dimeric IGF-I/IGFBP-1 complex in plasma (33) and thereby lower fasting free IGF-I concentrations (20, 34). In addition, we postulated that constant iv infusion of rhIGF-I would unmask E2- and Te-dependent control of dynamic adaptations of free IGF-I, IGFBP-1, and binary IGF-I/IGFBP-1 concentrations. To test these hypotheses, we studied healthy aging men and women, in whom IGF-I concentrations are relatively reduced (15, 16, 35); administered placebo (Pl) vs. E2 or Te in randomized order before each infusion; and used specific high-sensitivity immunofluorometric assays to quantitate total and ultrafiltrably free IGF-I, IGFBP-1 and the dimeric IGF-I/IGFBP-1 complex (see Subjects and Methods).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Overview

The effect of GHRH on GH secretion in these two studies was reported earlier (36, 37). The present analyses and measurements of IGF-I and IGFBP-1 do not overlap.

Subjects

The project was reviewed by the National Institutes of Health and Food and Drug Administration under an investigator-initiated new drug file for the use of rhIGF-I by iv infusion. Inclusion criteria required an unremarkable medical history and physical examination and normal outpatient screening laboratory tests of hepatic, renal, endocrine, metabolic, and hematologic function. Exclusion criteria included known or suspected cardiac, cerebrovascular, peripheral arterial, or venous thromboembolic disease; a history of chronic smoking; personal history of breast or endometrial cancer; elevated prostate-specific antigen and neoplastic or obstructive prostatic disease; concomitant or recent use of neuroactive medications; anemia; allergy to peanuts (in men due to the testosterone excipient); and failure to provide voluntary written informed consent. There was no recent transmeridian travel (within 10 d), night-shift work, significant weight change (≥2 kg in 6 wk), acute or chronic disease, psychiatric illness requiring treatment, or substance abuse. Some enrollees continued to take multivitamins and ferrous sulfate; one volunteer was using triamcinolone nasal spray and another was taking stable T4 replacement.

Eight postmenopausal and eight older male volunteers enrolled in and completed all four infusion sessions. Participants provided written informed consent approved by the institutional review board. In women, the mean (± SEM) age was 62 ± 3 yr and body mass index 25 ± 0.8 kg/m2. Individuals were clinically postmenopausal for at least 1 yr, and ovariprival status was confirmed by appropriate screening concentrations of FSH (>50 IU/liter), LH (>20 IU/liter), and estradiol (<20 pg/ml, < 7.4 pmol/liter). Subjects discontinued any sex hormone replacement at least 4 wk before participation. In men, the mean age was 61 ± 4 yr and body mass index 27 ± 1.3 kg/m2. Normal gonadal status was corroborated by unremarkable pubertal, fertility, and sexual histories; physical examination; and concentrations of LH (4.5 ± 0.8 IU/liter), FSH (7.8 ± 2.1 IU/liter), and total Te (439 ± 47 ng/dl or 15 ± 1.6 nmol/liter).

Protocol design

The design was a prospectively randomized, placebo-controlled, patient-blinded, within-subject crossover intervention. Each participant underwent a total of four admissions (two during placebo and two during estrogen or testosterone supplementation). Estrogen was administered orally twice daily for 10 d as 1 mg micronized 17ß-estradiol (Estrace; Bristol-Myers Squibb, Princeton, NJ) (15, 36). Testosterone was given as a single im injection of enanthate ester (300 mg in oil) (16). Each of four infusion sessions was performed on the morning of d 10 of Pl and sex steroid administration. Interventions were separated by a minimum of 6 wk. Thus, individual study duration was 4–6 months.

Volunteers were admitted to the General Clinical Research Center on the evening of d 9 of Pl or sex hormone administration to allow overnight adaptation to the unit. To obviate food-related confounds, subjects received a constant evening meal (turkey sandwich or vegetarian alternative) of 500 kcal containing 55% carbohydrate, 15% protein, and 30% fat at 1800 h. Participants remained fasting overnight and until 1400 h the next day. Caffeinated beverages, sleep, and vigorous exercise were disallowed during the sampling session.

Infusions

At 0600 h on the morning of study, iv catheters were inserted in (contralateral) forearm veins. Blood was withdrawn at 0600 h for later assay of E2 and Te concentrations and then sampled (2 ml) every 10 min for a total of 8 h (0600–1400 h). The 10-min samples were used to create hourly serum pools for measurements of free and total IGF-I, IGFBP-1, and dimeric IGF-I/IGFBP-1. After 2 h of baseline sampling (0600–0800 h), saline (50 ml/h) or rhIGF-I (10 µg/kg·h; Genentech, Inc., South San Francisco, CA) was infused continuously iv for 6 h during the interval 0800–1400 h. A single iv bolus of GHRH (1.0 µg/kg; Geref; Serono, Rockland, MA) was injected at 1200 h. The latter did not affect serial IGF-I concentrations in the presence or absence of IGF-I infusion. The time points after GHRH injection were included to establish a full time course of 6 h of rhIGF-I infusion. For safety monitoring, plasma potassium and phosphorus were measured at baseline and at the end of each infusion; the electrocardiogram was recorded continuously and plasma glucose concentrations hourly.

Hormone assays

Estradiol concentrations were quantitated in a single batch (32 samples) by double-antibody RIA with a sensitivity of 2.5 pg/ml and within-assay coefficient of variation (CV) of 4.8% (Diagnostic Systems Laboratories, Webster, TX). Total (acid-ethanol extractable) IGF-I concentrations were measured by time-resolved double-monoclonal immunofluorometric assay (20, 21). Sensitivity is 0.0025 µg/liter; IGF-II cross-reactivity is less than 0.0002%; and intraassay and interassay CVs are 3.2 and 8.6%, respectively. Free IGF-I concentrations were determined by the same means after centrifugal ultrafiltration of undiluted serum at 37 C (pH 7.4). The sensitivity is that of total IGF-I, and the precision is 5.3 (intraassay) and 9.8% (interassay) (38).

IGFBP-1 was determined by an in-house RIA performed according to Westwood et al. (39) with modifications as previously described (40). The RIA is based on a monoclonal IGFBP-1 antibody, which recognizes all human phosphoforms of IGFBP-1 in serum (MAB 6303; Medix Biochemica, Kauniainen, Finland). Iodinated rhIGFBP-1 served as tracer and unlabeled rhIGFBP-1 as standard (HyTest, Turku, Finland). The lower detection limit was estimated as approximately 2.5 µg/liter; half-maximal displacement occurred at 25 µg/liter; and the highest IGFBP-1 standard was 200 µg/liter. Within and between-assay CVs averaged 4.8 and 12%, respectively. Addition of rhIGF-I and -II (Austral Biologicals; San Ramon, CA) and rhIGFBP-2, -3, -4, and -5 (R&D Systems, Abingdon, UK) up to 10,000 µg/liter did not affect the measured concentration of IGFBP-1 to any significant degree.

The dimeric complex of IGF-I and IGFBP-1 was determined by a specific time-resolved immunofluorometric assay as previously described (33). The dimeric complex was captured by an IGFBP-1 antibody (MAB 6303) and detected by an Europium-labeled monoclonal IGF-I antibody (Diagnostic Systems Laboratories), prepared as previously described (21). The assay is highly specific for the dimeric complex of IGFBP-1 and IGF-I. No signal is obtained unless both IGF-I and IGFBP-1 are present, and none of IGFBP-2, -3, -4 or IGF-II caused any cross-reaction. Within- and between-assay CVs were 4.7 and 13%, respectively.

Rate estimates

The initial rate of progress of free or total IGF-I, IGFBP-1, or dimeric. IGF-I/IGFBP-1 concentrations toward equilibrium during rhIGF-I infusion was estimated as the slope of the corresponding linear regression on time (41, 42).

Statistical comparisons

One-way repeated-measures ANOVA was used to compare peptide concentrations. Subsequent post hoc contrasts were made using Tukey’s honestly significantly different criterion for multiple comparisons at an experiment-wise protected P = 0.05 (43). Unless otherwise indicated, P values reflect the overall interventional effect, unless further specified. Slope values were compared by cohort- and intervention-specific 95% statistical confidence intervals (44). Other data are given as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Doses of E2 and Te that are known to decrease and increase total IGF-I concentrations in postmenopausal women and older men, respectively were selected (15, 16). Compared with Pl, estrogen administration in women elevated concentrations of E2 from 4.4 ± 0.77 to 367 ± 28 pg/ml (to convert to picomoles per liter, multiply by 3.67), and Te supplementation in men increased Te concentrations from 439 ± 42 to 1043 ± 51 ng/dl (to convert to nanomoles per liter, multiply by 0.0347) (P < 0.01 for both).

Figure 1Go summarizes preinfusion (2-h baseline) concentrations of total (top) and free (bottom) IGF-I in the eight interventional settings. In the placebo context, fasting total IGF-I concentrations were lower in women than men (P = 0.013). Exposure to E2 decreased total and free IGF-I (both P < 0.025), whereas Te did not alter either measurement. Comparison of free IGF-I concentrations by gender showed that women receiving either Pl or E2 supplementation maintained higher values than men given Pl but not Te (P < 0.01).



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  		FIG. 1. Fasting preinfusion concentrations of total (top) and free (bottom) IGF-I in older men (n = 8) and postmenopausal women (n = 8) pretreated for 10 d with Pl, E2, or Te. Data are the mean ± SEM. The P value reflects the overall interventional effect. Means with unshared (unique) alphabetic superscripts differ significantly (see Results).

 
Figure 2Go presents the time course of total (A) and free (B) IGF-I concentrations monitored once each hour for 8 h in men (top) and women (bottom). Measurements were made twice before and six times during constant iv infusion of saline vs. rhIGF-I. Infusion of IGF-I elevated total and free IGF-I concentrations to consistently higher values in men than women after both Pl and sex steroid supplementation (P = 0.014). End-infusion values are compared statistically in Table 1Go. Note that the final total IGF-I concentration was higher after Te than Pl administration in men.



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  		FIG. 2. Time course of total (A) and free (B) IGF-I concentrations sampled every hour for 2 h before and 6 h during constant iv infusion of saline (50 ml/h) or rhIGF-I (10 µg/kg·h). Measurements were made after randomly ordered supplementation with Pl, E2, or Te. Data are the mean ± SEM (men, n = 8, and women, n = 8).

 

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  		TABLE 1. Maximal observed concentrations of total IGF-I, free IGF-I, IGFBP-1, and binary IGF-1/IGFBP-1 driven by constant infusion of rhIGF-I

 
Figure 3Go summarizes the initial rates (slopes) of increase of total and free IGF-I concentrations during saline and rhIGF-I infusion. Te, compared with Pl, administration increased the rate of rise of total IGF-I concentrations. Statistical analysis by gender revealed more rapid elevation of total IGF-I concentrations in Te-treated men than either E2 or Pl-exposed women (P < 0.05) and free IGF-I concentrations in men than women independently of steroid supplementation (P < 0.025).



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  		FIG. 3. Initial rates of rise (slopes) of concentrations of total (top) and free (bottom) IGF-I concentrations over time during saline and rhIGF-I infusion in men and women pretreated with Pl, Te, and E2. Statistical representations are described in Fig. 1Go.

 
Baseline concentrations and time courses of rising IGFBP-1 and binary IGF-I/IGFBP-1 complexes were compared by gender and sex steroid intervention. Principal similarities and distinctions included: 1) fasting concentrations of IGFBP-1 and IGF-I/IGFBP-1 were 1.4- and 1.7-fold higher in women than men given Pl (both P < 0.01) (Fig. 4Go); 2) E2 but not Te increased fasting IGFBP-1 concentrations significantly (P = 0.0062 within-gender); 3) E2 and Te increased dimeric IGF-I/IGFBP-1 concentrations significantly (both P < 0.05); 4) IGF-I infusion elevated IGFBP-1 (Fig. 5AGo) and dimeric IGF-I/IGFBP-1 (Fig. 5BGo) concentrations in both sexes; 5) the rate of increase in IGFBP-1 concentrations was independent of gender and sex steroid intervention (Fig. 6Go); 6) Te stimulated a 3.4-fold more rapid rise of binary IGF-I/IGFBP-1 concentrations than E2 (P < 0.01); and 7) men manifested an (unexplained) delay in the rhIGF-I-stimulated increase in dimeric IGF-I/IGFBP-1, and women did the same for monomeric IGFBP-1 concentrations.



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  		FIG. 4. Fasting concentrations of IGFBP-1 (top) and the binary IGF-I/IGFBP-1 complex (bottom) in men and women. See Fig. 1Go for data format.

 


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  		FIG. 5. Time profiles of IGFBP-1 (A) and binary IGF-I/IGFBP-1 (B) concentrations during continuous iv infusion of saline vs. rhIGF-I. Data are presented as described in the legend of Fig. 2Go.

 


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  		FIG. 6. Initial rates of rise (slope) of concentrations of IGFBP-1 (top) and binary IGF-I/IGFBP-1 (bottom) in men and women (see legend of Fig. 1Go).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present investigation disclosed that administration of E2, but not Te, lowers circulating free IGF-I availability and that this decrease is attributable to a significant rise in both IGFBP-1 and dimeric IGF-I/IGFBP-2 in fasting, healthy, middle-aged and older adults. In the setting of iv infusion of rhIGF-I, supplementation with Te, compared with E2, conferred higher final values of and more rapid elevations in the concentrations of free IGF-I and binary IGF-I/IGFBP-1. Based on these collective outcomes, we postulate that gonadal steroids can modulate the synthesis and/or metabolic clearance of IGF-I and IGFBP-1 differentially. In contrast, earlier studies (16, 45) indicated that IGFBP-3 concentrations are not influenced by E2 or Te supplementation.

An inverse relationship between IGFBP-1 and free IGF-I concentrations emerges in fasting and renal failure (increased IGFBP-1) as well as hyperinsulinemia and visceral obesity and after a high dose of GH (decreased IGFBP-1) (38, 46, 47). Such differences are important, inasmuch as low free IGF-I concentrations are associated with reduced somatic growth in puberty and, conversely, for high free IGF-I concentrations (48, 49). Accordingly, we postulate that higher free IGF-I concentrations in men than women receiving exogenous gonadal steroids may contribute to greater anabolism in men. The experimental finding that transgenic overexpression of IGFBP-1 impairs GH-stimulated growth in the immature hypophysectomized animal would support this notion (27). In murine models, the trimeric complex of IGF-I, acid-labile subunit and IGFBP-3 is also required for optimal growth (30, 34, 50, 51).

Constant iv infusion of rhIGF-I unveiled three salient contrasts between the effects of Te and E2. In particular, men with high physiological (mid to late puberty) Te concentrations, compared with women with high physiological (late follicular-phase) E2 concentrations, given rhIGF-I evinced higher peak free IGF-I concentrations and more rapid increases in free IGF-I and binary IGF-I/IGFBP-1 concentrations. Plausible bases for all three observations would be a smaller distribution volume for and/or shorter half-life of free IGF-I in men (52).

Infusion of rhIGF-I for 6 h stimulated greater than 3-fold increases in IGFBP-1 concentrations in men and women. Earlier clinical investigations indicate that infusion of rhIGF-I inhibits ß-cell insulin secretion rapidly (53). This effect may be pertinent, in that insulin represses hepatic IGFBP-1 gene transcription and lowers serum IGFBP-1 concentrations (46, 54).

Several caveats are relevant in interpreting the current outcomes. First, constant iv infusion of rhIGF-I over 6 h is a nonequilibrium intervention, described by initial rates of peptide distribution and elimination rather than by equilibrium half-lives (55). In the latter regard, earlier steady-state estimates of the half-lives of total IGF-I, free IGF-I, and binary IGF-I/IGFBP-I are 8–15 h, 12–18 min, and 25 min, respectively (50, 56). Whether equilibrium kinetics are altered by gender or sex hormones has not been ascertained. Second, the doses of E2 and Te used experimentally exceed physiological replacement. Actual threshold doses are not known in this type of model (48, 49). Third, in one study oral but not transdermal E2 replacement in postmenopausal women increased IGFBP-1 concentrations, and norethisterone inhibited this effect (32). Thus, extrapolation of our data to other hormone-replacement regimens would not be practicable. And fourth, the present assay configuration quantitates primarily, but not exclusively, high-affinity phosphorylated IGFBP-1 (33, 40). Whether comparable outcomes apply to the less abundant nonphosphorylated form is not known.

In summary, short-term administration of E2 in postmenopausal women diminishes the fasting concentration of free IGF-I and elevates that of IGFBP-1 and binary IGF-I/IGFBP-1. In contradistinction, Te supplementation in comparably aged men does not alter the fasting concentration of free IGF-I or IGFBP-1 but increases that of total IGF-I and binary IGF-I/IGFBP-1. Constant infusion of rhIGF-I induces higher final free IGF-I concentrations and more rapid increases in free IGF-I and binary IGF-I/IGFBP-1 concentrations in a Te-predominant than E2-enriched milieu. From these data, we postulate that sex steroids modulate the bioavailability of IGF-I in healthy adults.


   Acknowledgments
 
We thank Kris Nunez, Kimberly Coulter, Gail Bierbaum, and Kandace Bradford for excellent support of manuscript preparation; Dr. Peter O’Brien for statistical consultation; the General Clinical Research Center Core Assay Laboratory for performing the immunoassays and the nursing staff for conducting the research protocol; and Dr. Stacey Anderson, who screened, visited, and infused patients in the General Clinical Research Center on a fee-for-service basis.


   Footnotes
 
This work was supported in part by National Institutes of Health Grants MO1 RR00847 and RR00585 to the General Clinical Research Centers of the University of Virginia and Mayo Clinic and Foundation from the National Center for Research Resources (Rockville, MD); Grants R01 NIA AG14799 and AG19695 from the National Institutes of Health (Bethesda, MD); and the Hørslev Foundation, Danish Health Research Council (Grant 22020141), and Aarhus University-Novo Nordisk Center for Research in Growth and Regeneration.

First Published Online February 15, 2005

Abbreviations: CV, Coefficient of variation; E2, estradiol; IGFBP, IGF binding protein; Pl, placebo; rh, recombinant human; Te, testosterone.

Received July 7, 2004.

Accepted February 3, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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