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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 11 4013-4021
Copyright © 1998 by The Endocrine Society

Original Studies

Effects of Estradiol and Exogenous Insulin-Like Growth Factor I (IGF-I) on the IGF-I Axis during Growth Hormone Inhibition and Antagonism1

M. E. Wilson

Yerkes Primate Research Center, Emory University, Lawrenceville, Georgia 30043

Address all correspondence and requests for reprints to: Dr. Mark E. Wilson, Yerkes Primate Research Center of Emory University, Field Station, 2409 Taylor Lane, Lawrenceville, Georgia 30043. E-mail: markw{at}rmy.emory.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
In adult female monkeys, serum concentrations of insulin-like growth factor I (IGF-I) are decreased by estradiol replacement, whereas levels of IGF-binding protein-3 (IGFBP-3) are increased. Furthermore, chronic IGF-I supplementation elevates serum IGFBP-3 despite a suppression of GH. To better understand how estradiol and IGF-I affect the IGF-I axis, a series of three studies was conducted to examine how estradiol and GH interact to affect the IGF-I axis and how IGF-I regulates IGFBP-1 and -3 during GH inhibition or receptor antagonism in adult female rhesus monkeys. In Exp 1, adult ovariectomized females were studied during a 28-day baseline condition and a 28-day treatment condition in which females received a constant sc infusion of a somatostatin analogue (octreotide, Sandoz; SSa; 6 µg/kg·day) with a 14-day washout period separating the two conditions. Within each 28-day phase, females were studied for 14 days with no estradiol replacement and for 14 days with estradiol replacement (3 µg/kg·day, sc). Treatment with estradiol and SSa alone significantly lowered serum IGF-I compared with baseline. In contrast, estradiol and SSa given in combination resulted in a significant increase in serum IGF-I. Serum IGFBP-3 was significantly increased by estradiol and the combination of estradiol and SSa. The response of serum GH to the acute administration of the excitatory amino acid analogue, n-methyl-D,L-aspartic acid (5 µg/kg, iv) was not differentially affected by any of the treatments. In Exp 2, the effects of a GH receptor antagonist (Trovert, Sensus Corp.) was assessed in ovariectomized, young adult, treated females (GHa; 1.0 mg/kg, sc, weekly) and compared with that in untreated cohorts (Con) during 3 weeks of no estradiol and 3 weeks of estradiol replacement (3 µg/kg·day, sc). Serum IGF-I and IGFBP-3 were significantly suppressed in GHa compared with Con females. In Con females, estradiol replacement significantly decreased serum IGF-I and increased serum IGFBP-3. In contrast, estradiol replacement significantly elevated both serum IGF-I and IGFBP-3 in GHa females. In Exp 3, the effects of acute IGF-I administration (110 µg/kg, sc) were assessed during baseline conditions and during treatment with either GHa (1.0 mg/kg, sc, weekly) or SSa (16 µg/kg, sc infusion) in young adult females during no estradiol replacement and during estradiol replacement (3 µg/kg·day, sc). Acute IGF-I administration produced a similar net increase in serum IGF-I during baseline and GHa or SSa treatment. Although serum IGFBP-3 was significantly reduced by both GHa and SSa, acute treatment with IGF-I produced a significant elevation in IGFBP-3, peaking by 3 h after treatment before returning to baseline at 7 h. Estradiol replacement elevated serum IGFBP-1 under baseline conditions as well as during GHa and SSa treatments. However, changes in serum insulin in response to the feeding patterns during the acute treatment with IGF-I, predicted changes in serum IGFBP-1. As GH secretion was inhibited during SSa, acute IGF-I had little effect on serum GH. Although acute IGF-I significantly suppressed serum GH by 3 h after treatment during baseline, the hypersecretion of GH during GHa treatment was unaffected by acute IGF-I.

In conclusion, the results of the present analysis indicate that the effects of estradiol in postadolescent females on serum IGF-I are dependent on GH status, whereas estradiol consistently elevates serum IGFBP-3. Furthermore, acute IGF-I increases serum IGFBP-3 in females even during GH inhibition or receptor antagonism. Although overall serum concentrations of IGFBP-1 are elevated by estradiol and may be differentially affected by IGF-I treatment, acute changes in IGFBP-1 are more a consequence of changes in serum insulin in response to food intake. Taken together, these data suggest that IGFBP-3 is regulated by factors in addition to GH and that IGF-I can affect its own bioavailability by increasing circulating concentrations of IGFBP-3.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE DEPENDENCY of hepatic insulin-like growth factor I (IGF-I) synthesis and release on GH is well accepted (1, 2, 3). Not only does GH therapy to GH-deficient children stimulate IGF-I secretion (4), GH increases hepatic, skeletal, and epiphyseal IGF-I messenger ribonucleic acid (mRNA) in hypophysectomized rats (5, 6, 7). The facilitating effects of estradiol on IGF-I secretion in juvenile females is attributed to estradiol-induced increases in GH secretion (8, 9). Although estradiol effectively increases serum IGF-I in girls (10) and adolescent female monkeys (11), it suppresses serum IGF-I in postadolescent and adult females (12, 13, 14). This effect of estradiol could be due to a change in the GH signal (15) or to the hepatic response to GH (16, 17). However, other data suggest that estradiol diminishes IGF-I secretion in reproductive aged women despite normal GH secretion (18, 19). Indeed, estradiol suppresses hepatic IGF-I mRNA in adult rats (20), an effect dependent upon pretreatment with GH (21). No systematic data in primates are available that examine the interactive effects of estradiol and GH on IGF-I secretion.

IGF-I circulates bound to proteins, many of which have been identified and found to bind IGF-I with variable affinity (22). The majority of serum IGF-I is bound to IGF-binding protein-3 (IGFBP-3), which subsequently binds to an acid-labile subunit to form the 150-kDa ternary complex (1). IGFBP-3 also has a broad tissue distribution, but hepatic secretion determines circulating concentrations (22). Like IGF-I, IGFBP-3 synthesis and release are dependent upon GH (2, 3, 5, 7), and the facilitating effect of estradiol on IGFBP-3 secretion during adolescence (1, 11) and in adults (14) is thought to be mediated by GH. Indeed, estradiol replacement to adult female monkeys, which suppresses IGF-I concentrations, elevates serum IGFBP-3 (14). However, the effects of IGF-I on IGFBP-3 are more controversial. IGF-I stimulates IGFBP-3 mRNA (7, 23) and secretion (24) and decreases IGFBP-3 mRNA degradation in rats (25). In contrast, IGF-I therapy of patients with GH receptor deficiency does not increase IGFBP-3 (26, 27, 28, 29, 30), and serum IGFBP-3 is not elevated during short term IGF-I treatment in normal adults (31). However, serum IGFBP-3 is elevated in diabetic children receiving IGF-I by sc infusions (32) or daily injections for 1 month (33). Recently, it has been suggested that these inconsistencies may be due to the small number of subjects studied at different ages, different treatment regimens, and different analytical methods for IGFBP-3 (34). In contrast to these observations in humans, constant sc infusion of IGF-I consistently elevates serum IGFBP-3 in normal adolescent (11) and adult monkeys (14), whereas the acute administration of IGF-I produces a brief, but significant, increase in serum IGFBP-3 despite a suppression of GH secretion (11).

IGFBP-1, on the other hand, is thought to increase when IGF-I is acutely elevated (22). Although produced primarily in the reproductive tract and liver (35), serum IGFBP-1 is inversely related to insulin secretion (36). Consequently, any increase in serum IGFBP-1 by IGF-I is probably due to an IGF-I-induced decrease in insulin secretion (31). The relationship between IGFBP-1 and insulin suggests that IGFBP-1 may bind IGF-I to inhibit its insulin-like effects when insulin secretion is low (37). However, in addition to blocking the hypoglycemic effects of IGF-I (38), IGFBP-1 is increased in slowly growing children (39) and can inhibit IGF-I-induced growth in hypophysectomized rats (40) or when in molar excess of IGF-I (41).

To more fully define how the IGF-I axis is regulated in female primates, a series of three studies is reported that examines how estradiol and GH interact to affect circulating IGF-I and IGFBP-3 concentrations in adult females. Furthermore, we assessed whether IGF-I and estradiol interact to affect the generation of IGFBP-1 and -3 in the absence of GH activity. It was expected that estradiol would decrease serum IGF-I but increase IGFBP-3, even in the face of GH inhibition and receptor antagonism. Furthermore, it was expected that acute IGF-I would increase serum IGFBP-3 regardless of GH status and estradiol replacement, and that serum IGFBP-1 would parallel acute changes in IGF-I.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects were female rhesus monkeys (Macaca mulatta) born and raised at the Yerkes Primate Research Center. Females were housed indoors in pairs or small groups under a 12-h light, 12-h dark photoperiod and constant temperature (22 C) as described previously (42). Females were fed commercial monkey chow twice daily (Harlan Teklan Monkey Diet, Madison, WI) and fresh fruit once daily, and had continuous access to water. All protocols were approved by the Emory University institutional animal care and use committee in accordance with USDA and NIH policy and standards. The Yerkes Primate Research Center is fully accredited by the American Association for the Accreditation of Laboratory Animal Care.

All females used in these studies had been previously ovariectomized. Surgeries were performed while the animals were anesthetized with telazol (5 mg/kg, im) and supplemented with ketamine (5 mg/kg, iv, as needed). Animals were administered buprenorphine (0.01 mg/kg, im) and banamine (1 mg/kg, im, three times daily) postoperatively for analgesia. Continuous hormone administration was performed with osmotic minipumps (Alza Corp., Palo Alto, CA) implanted sc between the scapula while the animals were anesthetized. Pumps were removed and/or replaced as required by the specific protocol. Estradiol replacement was accomplished by implanting an estradiol pellet (Innovative Research of America, Sarasota, FL) sc between the scapula while the animals were anesthetized. The time release pellets were expended in a specified number of days and did not need to be removed. Studies were initiated after the females had been acclimated to the sampling procedures (43) to enable collection of blood samples from unanesthetized subjects (44). Unless otherwise stated, samples were collected between 0900–1000 h approximately 1 h after the morning meal to minimize the effects of food intake on the GH-IGF-I axis (45).

Exp 1: GH inhibition

The interactive effects of estradiol and the somatostatin analog octreotide (SSa; Sandoz, Hanover, NJ) on the GH-IGF-I axis were studied in five ovariectomized adult females (>8 to 11 yr of age). Females were studied during a 28-day baseline condition and a 28-day treatment condition in which females received a constant sc infusion (by osmotic minipump) of SSa (octreotide, Sandoz; 6 µg/kg·day), with a 14-day washout period separating the two conditions. Within each 28-day phase, females were studied for 14 days with no estradiol replacement and for 14 days with estradiol replacement (3 µg/kg·day, sc), which elevates serum concentrations to levels comparable to those in the midfollicle phase of an ovulatory cycle (42). In each treatment condition, serum samples were collected daily from days 3–7 and twice weekly thereafter. Samples were assayed for IGF-I, IGFBP-3, and estradiol. In addition, on day 11 of every treatment condition, each female was treated with the excitatory amino acid analog of glutamate, n-methyl-D,L-aspartic acid (NMDA; 5 mg/kg, iv), at time zero and 60 min, with samples collected every 20 min from -60 though 120 min. Samples were assayed for GH.

Exp 2: GH antagonism

The interactive effects of estradiol and a GH receptor antagonist, Trovert (Sensus Drug Development Corp., Austin, TX), on the GH-IGF-I axis were studied in 10 young adult females (40 months of age). Females were randomly assigned to a control group (Con; n = 5) or a group that received a weekly injection of Trovert (GHa; n = 5; 1.0 mg/kg, sc). Females were studied for 3 weeks with no estradiol replacement, for 3 weeks with estradiol replacement (3 µg/kg, sc), and for 1 week with no estradiol replacement. Samples were collected 3 days each week for IGF-I, IGFBP-3, and estradiol assays. Selected samples were assayed for GH and Trovert.

Exp 3: acute effects of IGF-I

The interactive effects of estradiol with either GH inhibition or GH antagonism in response to acute IGF-I administration were studied in 10 young adult females (46 months of age). Females were studied under 4 conditions: baseline (no estradiol replacement, undisturbed GH secretion), estradiol replacement only (undisturbed GH secretion), GH disruption (no estradiol replacement), and estradiol replacement plus GH disruption. Females were randomly assigned to the GH inhibition group (SSa; n = 5) or the GH antagonism group (GHa; n = 5). The estradiol dose (3 µg/kg·day) was the same as that used in Exp 1 and 2. GH inhibition was achieved by infusing a constant dose of octreotide (16 µg/kg·day) sc with an osmotic minipump (2ML2). GH antagonism was achieved by the weekly injection of Trovert (1.0 mg/kg, sc). On day 5 of each treatment phase, females receive an acute injection of IGF-I (110 µg/kg, sc; Genentech, Inc., South San Francisco, CA), and serum samples were collected at -24, 0, 1, 3, 7, 9, 12, 24, and 48 h relative to the IGF-I injection. Animals were fed 1 h before IGF-I treatment and again after the 7 h sample, but had food available throughout the sampling period. Day 5 was chosen as the data from Exp 1 and 2 indicated that GH secretion was affected by octreotide and Trovert, respectively, by that time. Samples were assayed for IGF-I, IGFBP-1, IGFBP-3, GH, insulin, and glucose, and selected samples from the GHa group were assayed for Trovert.

Assays

IGF-I was determined by a previously validated RIA in which the IGFBPs are neutralized with acid-glycine (13). The assay uses rhIGF-I (Peninsula Laboratories, Inc., Belmont, CA) as the standard and the iodinated ligand and a polyclonal IGF-I antibody (National Hormone and Pituitary Program). The assay has a sensitivity of 10 nmol/L, with inter- and intraassay coefficients of variation (CVs) of 6.9% (n = 19) and less than 5%, respectively. IGFBP-1 was determined with a commercially available immunoradiometric assay (Diagnostic Systems Laboratories, Webster TX). The assay has a sensitivity of 0.01 nmol/L, and inter- and intraassay CVs of 11% (n = 7) and less than 5%, respectively. IGFBP-3 was determined with a commercially available immunoradiometric assay (Diagnostic Systems Laboratories). The assay has a sensitivity of 6 nmol/L, and inter- and intraassay CVs of 18% (n = 7) and less than 5%, respectively. Estradiol was determined using a modification (46) of a commercially available RIA (Diagnostic Products, Los Angeles, CA). The assay has a sensitivity of 16 pmol/L and inter- and intraassay CVs of 12% (n = 49) and less than 5%, respectively. Insulin was determined with a commercially available RIA (Diagnostic Products) with a sensitivity of 2.5 IU/L and inter- and intraassay CVs of 14% (n = 20) and less than 5%, respectively. Serum glucose was determined using a colorometric assay (Sigma Chemical Co., Inc., St. Louis, MO). GH determinations for Exp 1 were performed with a previously validated RIA (13) that uses human GH as a reference (NIDDK hGH RP-1; 2.2 IU/mg) and iodinated ligand (AFP-11019B) and a polyclonal antibody against hGH (GH-2; National Hormone and Pituitary Program). This assay has a sensitivity of 0.30 µg/L and inter- and intraassay CVs of 8.2% (n = 25) and less than 5%, respectively. As the GH antagonist was used in Exp 2 and 3, a GH assay was developed in Dr. C. J. Strasburger’s laboratory that would show no cross-reactivity with the GH antagonist in a 10,000-fold excess of Trovert to endogenous GH in a sample (47). This sandwich assay employed two monoclonal antibodies that do not cross-react with the antagonist and had a linear working range from 0.2–60 µg/L for monkey GH, using human GH (International Reference Preparation 80/505) as the reference. Comparison of unspiked samples and to those spiked with up to 50,000 ng/mL Trovert showed that estimates of endogenous GH concentrations were unaltered by the addition of the GH antagonist (47). Monkey samples were diluted from 1:2 or 1:10 in normal sheep serum. To verify serum concentrations of Trovert, selected samples from Exp 2 and 3 were assayed for the GH antagonist using a modification of the previously described immunofunctional assay (48) in which Trovert molecules that retain binding site 2 for the GH receptor were recognized. Samples were diluted 1:100, and Trovert was used as the reference.

Analyses

Data within each experiment were expressed as the mean ± SEM for each treatment condition or group, as appropriate. Data were analyzed with ANOVA or covariance models for repeated measures. Contrasts to identify significant main or interactional effects of the categorical or repeated variable were made using post-hoc contrasts in which each mean was compared to the other means in the series (version 6.1, SPSS, Chicago IL) (49). The area under the response curve was calculated, using the trapezoid rule, to evaluate the responses to GHRH and NMDA. Regression analyses were also performed to evaluate the linear relationship between specified variables. All statistical tests with P <= 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Exp 1: GH inhibition

Estradiol replacement had a significant effect on the IGF-I axis, which was modified by GH inhibition. Serum IGF-I was significantly affected by the interaction of estradiol and GH inhibition (Fig. 1Go; F1,4 = 11.88). Treatment with SSa significantly reduced serum IGF-I compared to that under baseline conditions (20.2 ± 2.9 vs. 13.7 ± 1.6 nmol/L; F1,4 = 18.00). Estradiol replacement produced serum levels of IGF-I (16.9 ± 2.0 nmol/L) that were significantly lower than those observed during baseline (F1,4 = 7.04) yet higher than those observed during SSa treatment (F1,4 = 29.15). In contrast, treatment with estradiol and SSa combined resulted in serum levels of IGF-I (22.1 ± 3.6 nmol/L) comparable to baseline values (F1,4 = 0.22), but significantly greater than those observed during SSa alone F1,4 = 7.72). This differential effect of estradiol on serum IGF-I was not due to differences in serum estradiol, as concentrations were similar during baseline and SSa alone treatment (28 ± 3 vs. 26 ± 5 pmol/L) and were similar during estradiol alone and estradiol plus SSa treatments (284 ± 21 vs. 269 ± 30 pmol/L).



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  		Figure 1. Mean ± SEM serum IGF-I (upper panel) and IGFBP-3 (lower panel) in five adult female monkeys during baseline, estradiol (E2) replacement, SSa infusion, and combined E2 and SSa treatment.

 
Serum IGFBP-3 was significantly elevated by estradiol replacement treatment (Fig. 1Go). The dose of SSa did not affect serum IGFBP-3 compared to baseline (131 ± 9 vs. 134 ± 7 nmol/L, respectively; F1,4 = 0.50). In contrast, estradiol replacement significantly elevated serum IGFBP-3 when GH secretion was not inhibited (196 ± 10) or during combined treatment with SSa (199 ± 10 nmol/L; F1,4 = 21.95). The area under the curve for serum GH in the 60 min before NMDA administration (baseline, 109 ± 40 µg/L·min; estradiol, 115 ± 38 µg/L·min; SSa, 71 ± 28 µg/L·min; SSa plus estradiol, 92 ± 32 µg/L·min; F1,4 = 2.97) nor in response to NMDA administration (baseline, 214 ± 31 µg/L·min; estradiol, 210 ± 17 µg/L·min; SSa, 185 ± 30 µg/L·min; SSa plus estradiol, 201 ± 21 µg/L·min; F1,4 = 2.83) was not significantly affected by the treatment condition. However, serum GH was at the sensitivity of the assay (0.30 µg/L) in two females during both baseline and SSa treatment, but declined an average of 38 ± 13% during SSa treatment compared to the baseline value in the other three subjects.

Exp 2: GH antagonism

Treatment with the GH antagonist suppressed both IGF-I and IGFBP-3, but this effect was modified by estradiol (Fig. 2Go). Overall, serum IGF-I was significantly lower in GHa compared with Con females (F1,8 = 22.00), but was differentially affected by estradiol (F1,8 = 6.33). Within 3 days of the initiation of treatment, serum IGF-I was 61% lower in GHa compared to Con females, with levels maximally suppressed by day 10. Estradiol replacement resulted in an immediate suppression of IGF-I in Con females. In contrast, estradiol produced a significant elevation in IGF-I in GHa females, but to a level still below that in Con females. In both situations, this effect was limited to the first week of estradiol treatment, after which IGF-I concentrations gradually returned to preestradiol levels (F5,40 = 2.34). This effect of estradiol on IGF-I was not due to differences in serum estradiol between Con and GHa females (Fig. 2Go; F1,8 = 1.15). Levels of IGF-I in GHa females were again similar to those in Con animals 14 days after the cessation of GH antagonist treatment. Serum IGFBP-3 in GHa also declined by day 3 of treatment, with levels maximally suppressed by day 10 and remaining significantly lower throughout the study compared to those in Con females (Fig. 2Go; F1,8 = 18.46). Unlike IGF-I, serum IGFBP-3 was increased (F1,8 = 7.53) in a similar fashion (F1,8 = 0.05) by estradiol replacement in both Con and GHa females. However, by the third week of estradiol treatment, serum IGFBP-3 began to return to preestradiol levels (F5,40 = 8.24). As observed with IGF-I, serum IGFBP-3 returned to pretreatment levels 14 days after the cessation of GHa administration.



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  		Figure 2. Mean ± SEM serum IGF-I (upper panel), IGFBP-3 (middle panel), and estradiol (lower panel) in untreated females (Con; n = 5) and females treated weekly with a GHa (n = 5). Treatment with GHa is indicated by the arrows.

 
Serum GH concentrations were significantly elevated during GH antagonism (F1,8 = 33.91), and estradiol replacement increased levels in both groups (F1,8 = 33.61). Without estradiol replacement, serum GH was significantly higher in GHa (86 ± 11 µg/L) compared to Con females (15 ± 6 µg/L). Estradiol replacement elevated GH in both groups (GHa, 177 ± 25; Con, 28 ± 8 µg/L). Circulating concentrations of the GHa averaged 5379 ± 3316 µg/L (95% confidence interval). The regression of antagonist concentrations on average IGFBP-3 was significant (r8 = -0.86).

Exp 3: acute effects of IGF-I during GH inhibition or antagonism

Acute treatment with IGF-I elevated serum IGF-I concentrations in all groups (Fig. 3Go; F6,54 = 91.38) despite significant differences in serum levels among the baseline, SSa, and GHa treatment phases (F1,9 = 89.00). Although serum IGF-I was significantly lower during GHa compared with SSa treatment after IGF-I administration (F1,8 = 38.09), the pattern of the response was similar (F6,48 = 1.52). Estradiol replacement did not affect serum IGF-I levels in response to IGF-I treatment (F1,9 = 1.17). The net increase in serum IGF-I produced by IGF-I administration was similar during baseline (22.9 ± 2.0 nmol/L), SSa (23.1 ± 2.2 nmol/L), and GHa (20.6 ± 4.6 nmol/L), and serum IGF-I had returned to pretreatment levels by 9 h after IGF-I administration in all conditions.



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  		Figure 3. Mean ± SEM serum IGF-I (upper panel), IGFBP-3 (middle panel), and IGFBP-1 (lower panel) in response to an acute sc injection of IGF-I at time zero during baseline (n = 10), infusion with SSa (n = 5), and treatment with GHa (n = 5) in the absence of estradiol (no E2) and with estradiol (E2) replacement.

 
Serum IGFBP-3 was significantly reduced by SSa and GHa treatments compared to baseline values (Fig. 3Go; F1,9 = 13.32), with levels more suppressed by GHa than by SSa (F1,8 = 48.83). However, acute treatment with IGF-I significantly increased serum IGFBP-3 within 3 h of administration during baseline, SSa, and GHa conditions (F6,54 = 22.24) in a similar fashion (F6,54 = 0.56). Estradiol had no affect on the increase in IGFBP-3 in response to IGF-I (F6,54 = 0.78). The absolute increase in serum IGFBP-3 from concentrations before IGF-I administration to peak concentrations at 3 h was significant (F1,9 = 90.66), and the percent increase was similar during the baseline (8.3 ± 1.0%), SSa (11.1 ± 1.5%), and GHa conditions (10.0 ± 1.1%; F1,9 = 2.99). Serum IGFBP-3 returned to pretreatment levels between 7–9 h after IGF-I administration.

Serum IGFBP-1 was significantly elevated by estradiol (F2,9 = 36.16; Figs. 3Go and 4Go) in a similar fashion during baseline, SSa, and GHa treatment conditions (F1,9 = 0.04). Although estradiol replacement did not decrease serum insulin overall (F1,9 = 3.98), its effects did vary significantly with treatment phase (Fig. 4Go; F2,18 = 3.67), as serum insulin was decreased significantly by estradiol during baseline (F1,9 = 13.83) and SSa (F1,4 = 12.39), but showed little change from already low concentrations during GHa (F1,4 = 0.02). Treatment with GHa (F1,4 = 13.03) as well as SSa (F6,24 = 8.31) elevated serum IGFBP-1 compared with baseline levels. Although GHa produced a decrease in serum insulin compared to baseline levels (F1,4 = 6.35; P = 0.59), serum insulin was not altered by SSa compared to baseline levels (F1,4 = 0.51). Multiple regression analysis of serum IGFBP-1 before IGF-I administration (time zero) indicated that the combination of both treatment and serum insulin significantly predicted the variance in IGFBP-1 concentrations (r = 0.56; F2,37 = 8.42) more than either variable alone.



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  		Figure 4. Mean ± SEM serum concentrations of IGFBP-1 and insulin before IGF-I administration (see Exp 3) during baseline (n = 10), infusion of SSa (n = 5), and treatment with GHa (n = 5) in the absence of estradiol (no E2) and with estradiol replacement (E2).

 
Serum IGFBP-1 also changed significantly after acute IGF-I administration (Fig. 3Go; F6,54 = 11.32), but the pattern was quite different from that observed for IGFBP-3. Serum IGFBP-1 decreased by 3 h only to rise again by 7 h after IGF-I. As animals were fed 1 h before IGF-I administration and after the 7 h sample was taken, this change in IGFBP-1 was related to changes in serum insulin resulting from meal intake as well as IGF-I. However, under the present ad libitum feeding conditions, acute IGF-I administration did not have a consistent effect on serum insulin (F2,18 = 2.28). Nevertheless, the multiple regression analysis of serum IGFBP-1 3 h after IGF-I administration indicated that insulin alone significantly predicted the variance in IGFBP-1 concentrations (r = 0.33; F1,38 = 4.80), but that the addition of treatment condition to the equation did not increase the predictability significantly. Serum glucose was not significantly affected by IGF-I (F2,18 = 1.33) or by estradiol replacement (F1,9 = 0.20), with values ranging from 65–75 mg/dL.

Unlike IGFBP-3, the response of serum GH was quite variable and appeared to be dependent upon the coincidence of IGF-I administration with the timing of the GH pulse (Fig. 5Go). Although estradiol replacement increased pre-IGF-I treatment GH concentrations during baseline (15%), SSa (85%), and GHa (60%), it did not affect the response to IGF-I during either SSa (F1,4 = 0.01) or GHa (F1, 4 = 3.40) treatment compared to that at baseline. Compared to baseline conditions, serum GH was significantly lower during SSa infusion (F1,4 = 12.04), but was significantly higher during GHa (F1,4 = 6.22). As serum GH was inhibited during SSa treatment, acute IGF-I had little, if any, effect during SSa treatment (F1,4 = 1.56). As observed in Exp 2, serum GH was quite elevated during GHa treatment, and the dose of IGF-I used had little effect at the time periods sampled. In contrast, serum GH was significantly suppressed within 3 h of acute IGF-I administration during baseline conditions (F1,9 = 6.76). Finally, circulating concentrations of the GHa averaged 9604 ± 2321 µg/L. (95% confidence interval). The regression of antagonist concentrations with the average IGFBP-3 concentration was significant (r8 = -0.86).



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  		Figure 5. Mean ± SEM serum GH in response to acute IGF-I administration at time zero during baseline (n = 10), infusion of SSa (n = 5), and treatment with GHa (n = 5). Data for the no estradiol and estradiol replacement conditions were combined for each phase.

 
One GH receptor antagonist-treated subject did not show the same elevation in serum concentrations during the antagonist plus estradiol condition (469 U/mL). Indeed, her serum IGF-I (46 nmol/L) and IGFBP-3 (204 nmol/L) levels were significantly higher than her cohorts (Fig. 4Go). In addition, her serum insulin concentrations (151 U/L) were elevated compared to those in her cohorts (Fig. 5Go), but her serum glucose level (70 mg/dL) was similar (69 ± 3 mg/dL), suggesting that she had developed insulin resistance. Her data from this phase of the study were not used in the analysis. Consequently, the statistical program generated data for these missing values from her cohorts that were used in the analysis.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of the present series of experiments indicate that both estradiol and IGF-I can affect the IGF-I axis and that the effects can vary as a function of GH status. Estradiol replacement to these ovariectomized young and fully adult females significantly reduced serum IGF-I concentrations compared with those under baseline conditions. These data support observations in women (50, 51) and adult monkeys (14) that estradiol suppress IGF-I secretion and no longer stimulates IGF-I as its does during puberty (8, 10, 11). As reported in women (18, 19), these suppressive effects of estradiol on serum IGF-I observed in the present study were not associated with decrements in GH secretion. Indeed, estradiol increased serum GH in Exp 2 despite a concomitant fall in circulating IGF-I. These data suggest that there is an uncoupling of IGF-I secretion from GH induced by estradiol, a hypothesis that accounts for the decline in serum IGF-I observed in young adults (52, 53). The present analysis cannot address the mechanism that accounts for this suppression by estradiol. As the sampling frequency for GH secretion in the present studies was less than optimal, a change in the GH signal cannot be excluded. In addition, given that estradiol can directly inhibit IGF-I biosynthesis in the presence of GH in rats (20, 21), one could hypothesize that a similar effect occurs in adult primates. Thus, additional studies must determine how estradiol increases serum IGF-I in adolescent females yet decreases IGF-I in adult females during undisturbed GH conditions.

A quite unexpected finding of the present analysis was the increase in serum IGF-I by estradiol when given in combination with either the somatostatin analog or the GH receptor antagonist. This stimulation by estradiol during somatostatin analog infusion was constant throughout the 14-day treatment, whereas the increase during GH receptor antagonism occurred after the initiation of estradiol treatment when the highest estradiol concentrations were attained. However, as serum estradiol diminished with time, serum IGF-I declined towards preestradiol levels. These data in monkeys appear to be similar to those obtained in patients with GH receptor deficiency (54); serum IGF-I is low in adolescent patients, but is significantly elevated in adults with normal reproductive function. Although gonadal hormones were not measured in the GH receptor-deficient patients, the data suggest that estradiol or testosterone may be responsible for the increase in serum IGF-I in the face of GH receptor deficiency. Clinical conditions of GH receptor deficiency are functionally similar to the effects of treatment with a GH receptor antagonist, whereas the effects of somatostatin analog infusion are quite different. The only common feature is a diminution in GH action. Taken together with the data from estradiol replacement during undisrupted GH conditions, its appears that in the adult female, the prevailing GH milieu determines the effect of estradiol on hepatic IGF-I biosynthesis and secretion.

The facilitating effects of estradiol on serum IGFBP-3 could be mediated by an increase in GH secretion (11). However, unlike IGF-I, estradiol consistently elevated serum IGFBP-3 regardless of the prevailing GH milieu, suggesting that estradiol directly augments IGFBP-3 secretion. Data are not available that can elucidate the mechanisms by which estradiol has this effect. Estrogen receptors are not only found on hepatocytes where IGF-I is synthesized (55), but also in the nonparenchymal Kupffer cells where IGFBP-3 is synthesized (56). As GH stimulates IGFBP-3 Biosynthesis by inducing the release of a factor from the hepatocyte (57, 58), perhaps estradiol increases IGFBP-3 in a similar fashion. This speculation must be empirically verified. Furthermore, as the growth-promoting effects of IGF-I are potentiated by IGFBP-3 (59), a possible treatment strategy for improving the efficacy of IGF-I replacement in children with GH receptor deficiency may be the addition of low dose estradiol therapy to increase IGFBP-3 concentrations. Although the greatest growth potential using IGF-I occurs when the ternary complex forms (60), this is precluded during GH receptor antagonism or deficiency due to the absence of GH-induced increased in the acid-labile subunit (1). However, strategies to augment the formation of the binary complex may potentiate the effectiveness of IGF-I. Although the present data suggest that low dose estradiol supplementation would accomplish this, changes in skeletal maturity would need to be monitored to ensure that the growth plates do not close prematurely (61).

The results also indicate that acute IGF-I can increase IGFBP-3 concentrations independent of GH action. A significant elevation in serum IGFBP-3 occurred within 3 h of acute IGF-I administration during baseline or treatment with either a somatostatin analog or a GH receptor antagonist. Data from rodents indicate that IGF-I stimulates IGFBP-3 hepatic mRNA (7, 23) and secretion (24) and decreases IGFBP-3 mRNA degradation (25). Although IGF-I increases levels of IGFBP-3 in human fibroblast cultures without affecting mRNA (62), replacement therapy with IGF-I to GH receptor-deficient patients fails to consistently elevate serum IGFBP-3 (26, 27, 28, 29, 30). Furthermore, acute sc administration of IGF-I to normal humans produces a transitory increase in IGFBP-3, but overall concentrations are lower than those during saline treatment (31). However, the increase in serum IGFBP-3 after acute IGF-I administration observed in the present study is also seen in adolescent female monkeys (11) and supports observations that continuous sc infusion of IGF-I significantly elevates serum IGFBP-3 in monkeys (11, 14, 62, 63). In addition, serum IGFBP-3 is increased in children receiving a sc infusion of IGF-I for 10 h on 3 consecutive days (32) or repeated daily injections for 1 month (33). However, as these children were diabetic, caution must be exercised when comparing the data to the monkey studies. Future studies must reconcile this apparent discrepancy of the effects of IGF-I on serum concentrations of IGFBP-3 in humans (34). However, it is evident that regardless of GH status, IGF-I increases the serum concentrations of IGFBP-3, thereby potentially affecting its own bioavailability. Whether IGF-I has this facilitating effect on serum IGFBP-3 in female monkeys at the level of hepatic synthesis and release or by slowing IGFBP-3 degradation remains to be determined.

With respect to IGFBP-1, the present study clearly shows that estradiol replacement increases serum concentrations regardless of the prevailing GH status and, consequently, IGF-I status. As IGFBP-1 is inversely regulated by insulin (36), changes in serum IGFBP-1 must be balanced against changes in insulin secretion. Estradiol replacement reduced serum insulin during baseline and somatostatin analog infusion, but not during GH receptor antagonist treatment. Estradiol treatment of women has been shown to increase serum IGFBP-1 without any apparent change in circulating insulin concentrations (65), an effect attributed to increased output of IGFBP-1 by the ovarian follicles (36). However, as the subjects in the present study were ovariectomized, the increases in IGFBP-1 must be of hepatic origin.

The finding that estradiol did not affect serum insulin significantly during Trovert administration was probably due to the fact that serum insulin was already suppressed by the GH receptor antagonist treatment in the absence of estradiol, an effect associated with a significant increase in serum IGFBP-1. Although somatostatin analog infusion increased serum IGFBP-1 significantly above baseline, it did not alter serum insulin. The reduced concentration of serum insulin during GH receptor antagonist treatment is consistent with the fact that GH stimulates insulin secretion and increases insulin resistance (66, 67). Although octreotide treatment of normal men suppresses the increase in serum insulin in response to a meal (68), serum insulin was not altered by the somatostatin analog in the present study. Nevertheless, before IGF-I administration, the variance in serum IGFBP-1 was significantly predicted by the statistical combination of treatment condition and serum insulin. In contrast, the variance in serum IGFBP-1 after acute IGF-I administration was predicted only from insulin, not GH, status. These data underscore the importance of prevailing nutritional status and associated insulin concentrations on serum IGFBP-1. However, controlled metabolic studies are needed to assess how IGF-I administration affects glucose tolerance, insulin secretion, and IGFBP-1 concentrations when GH action is compromised in normal individuals.

The fact that octreotide treatment did not decrease GH concentrations in Exp 1 but did so effectively in Exp 3 is probably due to the dose used (6 vs. 16 µg/kg·day) as well as the age of the subjects and their basal serum GH levels (14). The elevated levels of serum GH resulting from GH receptor antagonist treatment are similar to those in patients with GH receptor deficiency (69). These high levels are due to an absence of GH negative feedback inhibition (70) because of blockage of the GH receptor and low IGF-I negative feedback. The acute treatment with IGF-I did not effectively suppress serum GH in antagonist-treated subjects as it did during the baseline phase of Exp 3 and in other experimental contexts (11, 71). Dose-response studies with IGF-I would have more fully described the negative feedback efficacy on GH secretion during Trovert administration.

Although estradiol replacement tended to increase GH secretion during octreotide infusion in postadolescent females (Exp 3), the absence of an effect of estradiol on GH secretion during octreotide infusion in adult females (Exp 1) may reflect the diminution in the GH secretory capacity that occurs with aging (72). In contrast, estradiol replacement enhanced GH secretion in both untreated and GH receptor antagonist-treated postadolescent females (Exp 2). These results indicate that estradiol does not facilitate GH secretion through a diminution in GH negative feedback, as GH receptors were blocked. Furthermore, it is unlikely that estradiol has this effect by reversing IGF-I negative feedback, as estradiol increased both GH and IGF-I during antagonist treatment. Rather, estradiol may facilitate GH secretion by enhancing the response to GHRH (73). In addition, it is also possible that estradiol may affect the GHRH neuron directly (74), so that exogenous stimulation with NMDA results in a greater release of GHRH and an increased GH response. To more critically evaluate the effects of estradiol on GH secretion during chronic somatostatin infusion or GH receptor antagonist treatment, extended frequent sampling regimens would be needed to characterize changes in the GH pulse.


   Acknowledgments
 
The technical assistance of Mara Lindsley, Susie Lackey, and Kathy Chikazawa is greatly appreciated. The reagents for the IGF-I assay were a gift from the National Hormone and Pituitary Program, NIDDK, NICHHD, and the USDA. IGF-I was a gift from Genentech, Inc., octreotide was a gift from Sandoz Pharmaceuticals Corp., and the GH antagonist Trovert was a gift from Sensus Drug Development Corp. I thank Drs. C. J. Strasburger, Dr. M. Bidlingmaier, and Z. Wu, Department of Medicine, Innenstadt University Hospital (Munich, Germany), for performing the GH assays in the GH antagonist studies as well as for providing useful comments on earlier drafts of this manuscript. All other assays were performed by Assay Services, Yerkes Primate Research Center.


   Footnotes
 
1 This work was supported by NIH Grant HD-16305 and in part by NIH Grant RR-00165. Back

Received June 11, 1998.

Revised July 31, 1998.

Accepted August 10, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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