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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 6 2018-2028
Copyright © 1998 by The Endocrine Society

Original Studies

Regulation of the Growth Hormone-Insulin-Like Growth Factor I Axis in Developing and Adult Monkeys Is Affected by Estradiol Replacement and Supplementation with Insulin-Like Growth Factor I1

M. E. Wilson

Yerkes Primate Research Center of 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
 Materials and Methods
 Results
 Discussion
 References
 
Developmental changes in the GH-insulin-like growth factor I (IGF-I) axis were evaluated in female rhesus monkeys to test the hypothesis that estradiol differentially regulates IGF-I secretion and molar ratios of IGF-I to IGF-binding protein-3 (IGFBP-3) from adolescence into adulthood and that estradiol can reestablish GH secretion in the face of enhanced IGF-I negative feedback inhibition of GH. Adult ovariectomized females were compared to ovariectomized adolescent females studied from 18–36 months of age, a period encompassing the juvenile phase through the expected age at first ovulation. A subgroup of adult (n = 5) and adolescent females (n = 5) was treated continuously with human IGF-I (110 µg/kg·day, sc) throughout the study period and were compared to age-matched, untreated adults (n = 5) and adolescent animals (n = 6). To further understand how IGF-I affects the GH-IGF-I axis, the acute response to IGF-I (100 µg/kg, sc) was assessed in adults and at two ages in developing females. Furthermore, all females were treated periodically with estradiol (4 µg/kg·day) to assess the effects on the parameters of the GH-IGF-I axis from adolescence into adulthood. Finally, the response to GHRH (1.0 µg/kg, iv) was assessed in adult females and in adolescent females at 18 and 24 months during no estradiol and estradiol replacement.

Serum IGF-I and IGFBP-3, in the absence of estradiol replacement, increased significantly throughout puberty before declining from late adolescence into adulthood. Supplementation with IGF-I resulted in a significant increase in both serum IGF-I and IGFBP-3 concentrations at all ages, although the effect was less in juvenile females. Nevertheless, the age-dependent increase and decline in IGF-I and IGFBP-3 were maintained in these supplemented animals. Estradiol replacement significantly increased both serum IGF-I and IGFBP-3 through adolescence, even in IGF-I-supplemented animals. However, with the transition from adolescence, estradiol suppressed serum IGF-I secretion, yet continued to increase IGFBP-3 in young adult and fully adult females. This change in proportionately less IGF-I compared with IGFBP-3 resulted in a significant age-dependent decrease in the molar ratio of IGF-I to IGFBP-3. Indeed, the molar ratio was highest during midadolescence, when both IGF-I and IGFBP-3 were at their zeniths. Serum IGFBP-1 was significantly higher in adolescent compared with adult females. However, estradiol replacement significantly elevated serum IGFBP-1 in adult, but not adolescent, females, abolishing the age differences observed under no estradiol conditions.

Serum GH was significantly higher in adolescent compared with adult females; levels in juvenile animals were intermediate. Replacement with estradiol significantly elevated serum GH in adolescent and adult females, particularly in females supplemented with IGF-I. In contrast, estradiol had no effect on serum GH during the juvenile phase. Supplementation with IGF-I significantly dampened the response to GHRH in young and fully adult females, but not in juvenile animals. However, estradiol replacement restored the response to GHRH in these adult, IGF-I-supplemented females.

These data indicate that in the absence of any ovarian influence, the decline in serum IGF-I and IGFBP-3 begins in postpubertal, young adult females and is not necessarily a consequence of old age. Furthermore, there is an age-dependent uncoupling of estradiol regulation of the GH-IGF-I axis, as estradiol stimulates GH and IGFBP-3 at all ages but increases serum IGF-I only during adolescent and decreases IGF-I in postpubertal, young adult females. Furthermore, IGF-I has a greater suppressive effect on GH secretion with advancing age, an effect reversed by estradiol replacement. These data suggest that the deficits in the GH-IGF-I axis observed in aged individuals may reflect a continuation of the regulatory changes that begin in young adult females.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ADOLESCENT growth and puberty in females are associated with an enhanced activity of the GH axis (1), including an increase in GH pulse amplitude (2) and a corresponding elevation in serum concentrations of insulin-like growth factor I (IGF-I) and its major serum binding protein (IGFBP-3) (3, 4, 5). In contrast, the activity of the GH axis is dampened in elderly women, characterized by a reduction in GH pulse parameters (6) and serum IGF-I and IGFBP-3 (7). Although these differences are quite evident between pubertal and aged individuals, changes in the GH axis may actually begin in the postadolescent period and continue through adulthood into senescence (8, 9, 10, 11). This implies that the mechanisms responsible for the robust synthesis and release of GH and IGF-I during maturation are gradually modified during the lifespan and may not simply reflect an impairment associated with old age.

Pulsatile GH secretion is regulated by the inhibitory action of somatostatin, which increases the interpulse interval, sensitizing the pituitary somatotrophs to subsequent GHRH stimulation and production of the GH pulse (12). Estradiol enhances GH pulse amplitude not only during maturation (2, 13), but also during ovulatory cycles in women (14). Furthermore, estradiol replacement therapy increases GH secretion in women with gonadal dysgenesis (15) and in postmenopausal women, but the effect occurs more consistently with oral rather than transdermal treatment (16, 17, 18). These facilitating effects of estradiol on GH secretion may be mediated through the hypothalamic synthesis and release of GHRH (19), as GHRH neurons bind estradiol (20) and GHRH gene expression increases from immaturity through adulthood (21) under positive regulation by gonadal steroids (22). The decline in GH secretion evident in postmenopausal women is associated with a corresponding decrease in serum estradiol (23). As the decrements in GH secretion that occur in aged individuals have also been attributed to impaired GHRH secretion (11, 24, 25), it is possible that postmenopausal declines in estradiol account for deficits in GHRH secretion. However, estradiol replacement enhances GHRH-induced GH release only in agonadal premenopausal (26), not in postmenopausal women (18, 27). In addition, the decrease in GH secretion in premenopausal women occurs despite otherwise normal estradiol levels (10), suggesting that mechanisms in addition to diminished estradiol levels may affect the decline in GH secretion from maturation into adulthood.

One such mechanism that may participate in this decline is IGF-I negative feedback action on GH release. IGF-I inhibits pulsatile GH release (28) by decreasing GH messenger ribonucleic acid (mRNA) and the response to GHRH in vitro (29). Furthermore, both GH and IGF-I decrease hypothalamic GHRH gene expression during maturation (30) and somatostatin content in adult males (31). However, it is not known whether there is an age-dependent change in the ability of IGF-I to suppress GH secretion. A recent study suggests that an increased sensitivity to IGF-I negative feedback does not account for deficits in GH secretion in aged individuals, as IGF-I infusion suppressed pulsatile GH similarly in young and aged adults (32). However, changes in IGF-I negative feedback may be an important mechanism regulating GH secretion from adolescence to adulthood and into senescence.

In contrast to the consistent facilitory effects of estradiol on GH secretion, estradiol regulation of the IGF-I axis appears to change with age. The rise in serum IGF-I and IGFBP-3 during female puberty is the result of an increase in circulating estradiol (33, 34, 35, 36) mediated through a steroid-dependent increase in GH secretion (2) and hepatic GH receptor synthesis (37). Some studies indicate that IGFBP-3 is GH dependent (38, 39); however, IGF-I administration increases serum IGFBP-3 (36, 40, 41), and IGF-I normalizes IGFBP-3 mRNA in GH deficiency (42). Regardless, the developmental elevation in serum IGF-I and IGFBP-3 begins to decline as females reach adult status (3) despite robust gonadal function (43). Thus, although estradiol facilitates IGF-I secretion in adolescent females (36, 44), oral estrogens may lower serum IGF-I (45), and estrogen replacement to aged females either suppresses or has no effect on serum IGF-I and IGFBP-3 despite augmenting GH secretion (16, 17, 18, 46). However, one study reports that transdermal, but not oral, estrogen increases serum IGF-I in postmenopausal women (17). Importantly, however, the GH-induced increase in serum IGF-I is diminished by estradiol in older women (47). Consequently, there appears to be an uncoupling in the regulation of GH and the IGF-I axis by estradiol with advancing age, and this may occur long before the onset of senescence.

The present study was designed to test the hypothesis that the effects of estradiol and IGF-I on the GH-IGF-I axis vary through adolescence into adulthood and that these changes are evident in older, nonaged females compared to actively growing adolescents. Developmental changes in the GH-IGF-I axis in response to a constant infusion of IGF-I and to periodic estradiol replacement therapy were studied longitudinally from preadolescence through the expected age of sexual maturity in ovariectomized rhesus monkeys and were compared to the effects of IGF-I and estradiol in ovariectomized adult females. The interactive effects of estradiol, IGF-I, and age on the pituitary response to GHRH were also assessed. The results indicate that the robust secretion of the GH-IGF-I axis observed during adolescence is decreased in young adult females and that these changes persist into adulthood. Furthermore, the effects of estradiol and IGF-I are age dependent, as estradiol is less effective in stimulating the GH-IGF-I axis, and IGF-I is more effective in suppressing GH release in adult compared with adolescent animals.


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

Subjects were female rhesus monkeys (Macaca mulatta) housed at the Yerkes Primate Research Center of Emory University. The Yerkes Primate Research Center is fully accredited by the American Association for the Accreditation of Laboratory Animal Care. Animals were socially housed indoors in large cages (n = 4/cage) or in paired cages (n = 2) under a 12-h light, 12-h dark cycle and constant temperature range of 22–25 C, as described previously (48). Animals were fed commercial monkey chow (Harlan Teklan Monkey Diet, Madison, WI) ad libitum twice daily and fresh fruit once daily, and had continuous access to water. The experimental protocol was approved by the Emory University animal care and use committee in compliance with all NIH and USDA standards.

Procedures

Adult females (n = 10) were 9.5 ± 0.6 yr of age at the beginning of the study. Data collection for these females was completed in 10 months. Adolescent females (n = 11) were studied from 18–36 months of age. All females were ovariectomized 1 month before the initiation of data collection. Ovariectomies were performed by the attending clinical veterinarian while the animals were under general anesthesia. Females were randomly assigned to a control group or to a group that received a constant sc infusion of recombinant human IGF-I (Genentech, South San Francisco, CA) at a dose of about 110 µg/kg·day (49). IGF-I was infused with osmotic minipumps (Alza Corp., Palo Alto, CA), which were implanted, under sterile conditions, sc between the scapula while the animals received general anesthesia. Pumps were changed every 28 days or more frequently if needed. Consequently, the resulting treatment groups were as follows: adult control (n = 5); adult, IGF-I treated (n = 5); adolescent control (n = 6); and adolescent, IGF-I treated (n = 5). For comparative purposes, females were classified developmentally, corresponding to specific ranges in serum LH levels that are observed during puberty in rhesus monkeys (49): 18- to 24-month-old animals were defined as juvenile (LH, <0.38 ng/mL), 25- to 31-month-old animals were defined as early adolescent (LH, 0.38–6.50 ng/mL), and animals 32 months of age or more were defined as young adult (LH, >=6.50 ng/mL). Without estradiol treatment, LH concentrations in adults were greater than 6.50 ng/mL. For gonadally intact females, these periods correspond to premenarche (<24 months), postmenarche (24–32 months), and after the first ovulation (>32 months) (48).

To evaluate the effects of estradiol replacement on parameters of the GH-IGF-I axis, females were treated periodically with estradiol (Innovative Research of America, Sarasota, FL) to produce physiological concentrations comparable to those during the follicular phase. These concentrations were achieved by implanting pellets (~80 µg/kg) that would yield a dose of 4 µg/kg·day over the 21-day treatment period. For adults, the 21-day estradiol treatments were separated by at least 42 days of no estradiol treatment. Adolescent females initially received estradiol treatments at 18 and 22 months of age to assess how the GH-IGF-I axis responded during early puberty. Periodic estradiol treatment, occurring every 50 days, was initiated at about 26 months of age, corresponding to the developmental period when serum LH was increased significantly (49). Consequently, females were studied under estradiol and no estradiol treatment conditions at the same developmental stage. Serum samples were collected twice weekly for adults and weekly through 20 months of age and twice weekly thereafter for adolescent females using procedures previously described (48). Importantly, all subjects were habituated to the procedures so that samples could be obtained from unanesthetized animals in a minimal amount of time (<2 min). All samples were obtained 60–90 min after the morning meal. Samples from each developmental phase were assayed for estradiol, IGF-I, and IGFBP-3. Selected samples were also assayed for IGFBP-1.

To further understand the age-dependent effects of IGF-I, developmental differences in the acute response to IGF-I were assessed in the control, untreated adult females (n = 5) upon completion of data collection and in adolescent females (n = 6) at 23 and 36 months of age. After the morning meal, each female received 100 µg/kg IGF-I, sc, and samples were collected before treatment (time zero) and 1, 3, 7, 9, 12, and 24 h after treatment. The afternoon meal occurred between the 7 and 9 h sample collections. Females were not treated with estradiol during these acute assessments. Samples were assayed for IGF-I, IGFBP-1, IGFBP-3, and GH.

Estimates of developmental changes in basal GH secretion were obtained from samples collected every 20 min for 60 min under no estradiol and estradiol replacement at four ages during adolescence and twice in adults. The developmental response to GHRH was assessed at two ages in adolescent females under no estradiol and estradiol treatment (~18 and ~34 months of age) and in adults during both no estradiol and estradiol phases. At each assessment, females received GHRH (1.0 µg/kg, iv; Peninsula Laboratories, Belmont, CA). Samples were collected by venipuncture every 20 min from -60 through +120 min relative to the injection and were assayed for GH.

Analyses

Serum concentrations estradiol were determined by RIA, using commercially available reagents (Diagnostic Products Corp., Los Angeles, CA) as described previously (48). Total serum concentrations of IGF-I and GH were determined using a RIA validated for the monkey (50). IGFBP-1 and IGFBP-3 were measured by commercially available immunoradiometric assays (Diagnostic Systems Laboratory, Webster, TX). As the IGFBP-3 assay also recognizes IGFBP-3 fragments, previously unthawed samples were assayed to minimize protein degradation and protease activity. To calculate the molar ratio of IGF-I to IGFBP-3, a molecular weight of 7.3 kDa was used for IGF-I, and 54.5 kDa was used for IGFBP-3. To confirm specific developmental stages, serum LH was determined using monkey reagents as described previously (51).

Group data were expressed as the mean ± SEM, and differences were evaluated by ANOVA models (SPSS for the Macintosh, SPSS, Chicago, IL). For analysis purposes, adolescent females were compared to themselves developmentally, with age and estradiol replacement as repeated measures and IGF-I supplementation as a categorical variable. Additional analyses compared parameters of the GH-IGF-I axis in adults to those in adolescents at specific ages, with estradiol replacement as the repeated measure and age and IGF-I supplementation as categorical variables. Significant interactional effects (how treatments varied with age) were further evaluated by Scheffe’s post-hoc tests or simple main effects derived from the ANOVA model. Responsiveness to GHRH stimulation was analyzed by calculating the area under the curve using the trapezoid rule. Values were transformed by log10 to normalize the distributions. Statistical tests that yielded P <= 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
IGF-I axis

Serum levels of IGF-I, in the absence of estradiol treatment, varied significantly with increasing age through adolescence (F6,54 = 13.28), with the lowest concentrations at 18 and 35 months of age and the highest levels between 24–30 months of age (Fig. 1Go). Although adults did not differ significantly from adolescent females at 18 and 20 months of age (F1,17 <= 2.45), serum IGF-I was significantly lower in adults compared to levels during all other adolescent periods (F1,17 >= 12.46). In addition, IGF-I administration significantly elevated serum IGF-I throughout adolescence (F1,9 = 13.01) and in adults (t8 = 4.25), and this facilitory effect of IGF-I supplementation did not vary with age (F1,17 <= 1.57). Thus, without any influence of estradiol, IGF-I concentrations increased throughout adolescence before declining during the postadolescent period into adulthood, and the sc infusion of 110 µg/kg·day IGF-I consistently elevated serum IGF-I in all females, regardless of age, to approximately 88.7% above that in untreated animals.



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  		Figure 1. Serum concentrations (mean ± SEM) of IGF-I (upper panel) and IGFBP-3 (lower panel) in untreated control (open symbol) and IGF-I-supplemented (closed symbol) adult and adolescent females from 18–35 months of age. Data represent the average of the 3 weeks of pump infusion at each age in IGF-I-treated females or a comparable period in untreated females. All data were derived from periods without estradiol replacement.

 
Serum IGFBP-3 also varied significantly during adolescence in the absence of estradiol (F6,54 = 39.50), with highest levels at 26 and 30 months and lowest levels at 18 months of age (Fig. 1Go). Concentrations of IGFBP-3 did not vary among the other ages. Unlike serum IGF-I, concentrations of IGFBP-3 were significantly higher in adults compared to those in 18-month-old adolescents (F1,17 = 25.14), significantly lower than those in adolescents at 26 and 30 months (F1,17 >= 5.69), and similar to those in adolescents at the other ages (F1,17 <= 1.00). Importantly, IGF-I administration elevated serum IGFBP-3 levels, compared to those in nonsupplemented females, in adults (t8 = 3.71) and at all adolescent ages except 18 and 20 months (F6,54 = 5.11). Serum IGFBP-3 resulting from IGF-I supplementation was significantly higher in adults compared to adolescents at 18 and 20 months of age (F1,17 >= 5.06), was significantly lower in adults compared to adolescents at 26 months of age (F1,17 = 6.22), and was similar in adults and adolescents at all other ages (F1,17 <= 3.70).

Estradiol affected serum IGF-I, even in females supplemented with IGF-I, in an age-dependent manner (Fig. 2Go). Estradiol concentrations (indicated in Fig. 2Go) did not differ between control and IGF-I females, but were elevated to the same range by estradiol replacement. Estradiol replacement significantly elevated serum concentrations of IGF-I during the juvenile (F2,18 = 20.49) and early adolescent (F2,18 = 5.48) periods, and this facilitory effect was significantly greater during early adolescence than during the juvenile period (F4,36 = 10.02). In contrast, estradiol replacement significantly decreased serum IGF-I in young adult (F2,18 = 14.97) and adult (F2,16 = 16.13) females. Importantly, the age-specific effect of estradiol was not influenced by cotreatment with IGF-I during adolescence, as serum IGF-I followed the same pattern in IGF-I-treated compared with control females (F4,36 = 1.88). Despite these effects of estradiol, the difference in serum IGF-I was consistently higher in IGF-I-treated compared with control adolescents (F1,9 = 4.98). In adult females, serum IGF-I decreased similarly during estradiol replacement in both control and IGF-I-treated animals, but increased significantly after the cessation of estradiol in IGF-I-treated subjects (F2,16 = 10.28). Thus, serum IGF-I is increased by estradiol during adolescence, but is decreased in young and fully adult females.



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  		Figure 2. Serum concentrations (mean ± SEM) of IGF-I before, during, and after low dose estradiol replacement in untreated control (open symbol) and IGF-I-supplemented (closed symbol) adult and adolescent females at three developmental phases. The period of estradiol treatment is indicated by shading. The mean ± SEM serum estradiol concentrations (picomoles per L) are listed during each phase for every age group. As a point of reference, the dashed line represents the average IGF-I concentrations (500 ng/mL) observed in juveniles during estradiol replacement.

 
In contrast to the age-specific effect on IGF-I, estradiol replacement elevated serum IGFBP-3 at all ages (Fig. 3Go). The increase in serum IGFBP-3 produced by estradiol treatment was significant during the juvenile (F2,18 = 67.89), early adolescence (F2,18 = 34.59), and young adult (F2,18 = 9.32) periods as well as in adults (F2,16 = 95.15). Furthermore, this effect of estradiol on serum IGFBP-3 was similar in control and IGF-I-treated females through the young adult period (F4,36 < 1.00), yet levels of IGFBP-3 were consistently higher in IGF-I-treated animals (F1,9 = 7.91). Although estradiol elevated serum IGFBP-3 in IGF-I-supplemented females, the increase produced by the steroid replacement was greater in non-IGF-I-treated animals (F2,16 = 39.00).



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  		Figure 3. Serum concentrations (mean ± SEM) of IGFBP-3 before, during, and after low dose estradiol replacement in untreated control (open symbol) and IGF-I-supplemented (closed symbol) adult and adolescent females at three developmental phases. The phase of estradiol treatment is indicated by shading.

 
This differential effect of estradiol on the IGF-I axis resulted in a decrease in the molar ratio of IGF-I to IGFBP-3 from early adolescence through adulthood (Fig. 4Go). In the absence of estradiol, IGF-I administration increased the molar ratio significantly at all stages of development (F2,18 = 8.49) and in adults (F1,8 = 12.34). However, given the age-specific effects of estradiol on IGF-I and IGFBP-3 secretion, estradiol replacement increased the molar ratio only during early adolescence, whereas the ratio declined with estradiol treatment during the juvenile and young adult periods (F2,18 = 8.31) as well as in fully adult females (F1,8 = 13.57). Importantly, overall ratios were lower in adults compared to those in young adults (F1,17 = 16.12) and during the young adult period compared to those in early adolescence and the juvenile period (F2,18 = 6.97). The age-specific decline in the molar ratio reflects proportionately less IGF-I compared to IGFBP-3 in young and fully adult females.



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  		Figure 4. Serum molar ratios (mean ± SEM) of IGF-I to IGFBP-3 during no estradiol and low dose estradiol replacement in untreated control (open symbol) and IGF-I-supplemented (shaded symbol) adult and adolescent females at three developmental phases.

 
Selected samples were analyzed to determine whether serum IGFBP-1 varied significantly as a function of IGF-I and estradiol and between adult and adolescent females at 30 months of age. IGF-I supplementation had no effect on IGFBP-1 concentrations (data not shown; F1,17 = 2.85). However, serum IGFBP-1, in the absence of estradiol replacement, was significantly higher in adolescent (98 ± 7 ng/mL) compared with adult females (49 ± 11 ng/mL; F1,17 = 15.08). In contrast, estradiol replacement significantly elevated IGFBP-1 concentrations in adult (144 ± 11 ng/mL), but not adolescent (104 ± 7 ng/mL) females, such that serum levels were significantly higher in adult animals (F1,17 = 12.05).

Acute response to IGF-I

Acute treatment with IGF-I showed that the GH-IGF-I axis is differentially affected by IGF-I as a function of age (Fig. 5Go). Baseline (time zero) IGF-I values were significantly higher in young adults than values obtained during the juvenile phase (t5 = 3.62) or in adults (t9 = 2.50). The pattern of serum IGF-I during the initial response phase (1–7 h) varied significantly during the juvenile compared to the young adult period (F2,10 = 8.31), with significantly higher levels in young adults. However, when values were expressed as the percent change from time zero, concentrations through +7 h were significantly increased above baseline in juvenile (94 ± 24%) compared with young adults (38 ± 12%; t5 = 2.57). During the remaining period (9–24 h), serum IGF-I did not differ between juvenile and young adults (F3,15 = 2.50). The response to acute IGF-I in adults was intermediate between juvenile (F1,9 < 1.00) and young adult (F1,9 = 1.50) females. However, given the lower baseline value in IGF-I for the adults, the percent change during the initial period was significantly greater in adults (104 ± 15%) than in young adults (t9 = 3.50), but was similar to that in juveniles.



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  		Figure 5. Serum concentrations (mean ± SEM) of IGF-I (upper panel), IGFBP-3 (second panel), GH (third panel), and IGFBP-1 (lower panel) in adolescent females (n = 6), during the juvenile phase (~23 months), in young adults (~36 months), and in adults (n = 5) after the acute administration of IGF-I (100 µg/kg, sc) at time zero.

 
Although baseline IGFBP-3 levels did not differ among the three age groups (Fig. 5Go), serum levels varied significantly during the initial response phase in adult compared to both juvenile (F2,18 = 4.36) and young adult (F2,18 = 13.24) animals, but not between juvenile and young adult females (F2,10 < 1.00). Inspection of the data indicated that IGFBP-3 concentrations were significantly higher in adults than those in younger animals from 3–12 h after acute IGF-I treatment. Indeed, the percent change from time zero was greater in adults (14 ± 2%) than in either juvenile (7 ± 2%; t9 = 2.51) or young adult (7 ± 5%; t9 = 2.26) females. The concentrations of IGFBP-3 did not vary among the groups during the later response phase. Finally, the molar ratio of IGF-I to IGFBP-3 during the 24-h response period was significantly lower in adults (0.300 ± 0.022) than that in young adults (0.367 ± 0.026; t9 = 2.32), with an intermediate value in juvenile females (0.326 ± 0.017).

Although time zero concentrations of GH were similar among the three groups (Fig. 5Go), the patterns differed significantly after acute IGF-I treatment. IGF-I resulted in a decrease in serum GH by +1 h in all females. However, GH levels remained suppressed in adult females thereafter, being significantly lower throughout than levels in juvenile animals (F1,9 = 42.84). Although serum GH was significantly lower in adults than in young adults during the initial response phase (F1,9 = 7.28), the pattern of GH varied significantly from +9 through +24 h between the two groups given the fluctuation in GH for the young adult females (F2,18 = 5.16). Finally, serum GH was similar between juvenile and young adults during the initial response phase (F1,5 = 3.74), but was significantly lower in young adult females thereafter (F1,5 = 6.74).

With respect to serum IGFBP-1, baseline levels were significantly higher in juvenile compared with young adult (t5 = 5.64) and adult (t9 = 6.72) females, with values in young adults higher than those in adults (t9 = 2.81). After acute IGF-I treatment, IGFBP-1 in adults increased before declining to baseline levels by +7 h, such that levels were significantly lower than those in either juvenile (F1,9 = 22.31) or young adult (F1,9 = 22.09) females. IGFBP-1 decreased in both juvenile and young adult females, but the magnitude of the decrease was greater in juvenile animals (F2,10 = 4.96). By +12 h, concentrations were again significantly higher in juveniles than those in young adults (F2,10 = 5.91).

Response in serum GH

Although baseline GH concentrations (Table 1Go) were greater in adolescent compared to adult females (F1,17 = 4.72), with juvenile animals having intermediate levels (F1,17 < 1.00), IGF-I administration and estradiol replacement produced differential effects on serum levels during the course of development. Despite lower baseline serum GH in IGF-I-treated compared to control females in each age category, differences were significant only in young adults (t9 = 2.51). Estradiol had a greater facilitory effect on basal GH levels in young adults (F1,9 = 8.26) and in adults compared with the juvenile animals (F1,17 = 8.50). However, this effect of estradiol was most evident in IGF-I-treated females, as estradiol replacement reversed the suppressive effects of IGF-I on GH levels in young (F1,9 = 7.93) and fully adult (F1,8 = 8.00) females. Estradiol had little effect on baseline GH in juveniles.


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  		Table 1. Mean ± SEM serum GH concentrations at baseline and the area under the GH curve in response to GHRH (1.0 µg/kg, iv) during no estradiol and during replacement with low dose estradiol for adult and adolescent females at two developmental ages, juvenile (18/22 months) and young adult (33/35 months)

 
The response in serum GH to GHRH also varied with age as a function of estradiol replacement and IGF-I supplementation (Table 1Go and Fig. 6Go). Estradiol replacement significantly increased the response to GHRH in adult compared with both juvenile (F1,17 = 39.47) and young adult (F1,17 = 26.19) females, but not in juveniles compared with young adults (F1,9 < 1.00). Importantly, IGF-I supplementation dampened the response to GHRH in the adult animals, an effect reversed with estradiol replacement. Although the response to GHRH was significantly reduced by IGF-I supplementation in adults compared to those in juveniles and young adults, cotreatment with estradiol improved the response in adults compared to juveniles (F1,17 = 16.30) and young adults (F1,17 = 5.22). Furthermore, IGF-I supplementation significantly decreased the response to GHRH in young adult compared to juvenile animals (F1,9 = 15.96); however, estradiol did not differentially improve the response between these two groups (F1,9 = 3.08). Thus, IGF-I supplementation dampens the response of GH to GHRH in adult and young adult females, an effect that is reversed by estradiol in fully adult females.



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  		Figure 6. Representative graphs of serum GH in response to GHRH (1.0 µg/kg, iv) at time zero for adult (Ax) and adolescent control (26 months; Px) female and for an adult (Ax-i) and an adolescent (Px-i) female treated with IGF-I during no estradiol and estradiol treatment phases.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of the present study indicate that serum IGF-I and IGFBP-3 increase throughout puberty before declining in late adolescence into adulthood. Estradiol has a facilitory effect on both serum IGF-I and IGFBP-3 during maturation, but with the transition from adolescence, estradiol suppresses serum IGF-I secretion, yet continues to increase IGFBP-3. This change results in an age-dependent decrease in the molar ratio of IGF-I to IGFBP-3. Supplementation with IGF-I results in a significant increase in both serum IGF-I and IGFBP-3 concentrations at all ages, although the effect is less in juvenile females. In addition, IGF-I dampens both spontaneous and GHRH-stimulated serum GH concentrations more in adult than in juvenile females, and this effect is reversed by estradiol replacement.

These data support observations in humans that IGF-I and IGFBP-3 increase during maturation and decrease into adulthood (3, 4). This decrease in the IGF-I axis began in postpubertal, young adult animals and continued in fully adult females. As this pattern occurred without any effect of estradiol, the data support previous observations of a nongonadal component to the regulation of the IGF-I axis in females (35). Furthermore, this developmental pattern also occurred in IGF-I-supplemented monkeys, as IGF-I treatment merely elevated serum IGF-I at all ages and elevated serum IGFBP-3 at all but the youngest age. In addition, the present data confirm that estradiol replacement enhances this developmental increase in both IGF-I and IGFBP-3 during adolescence (33, 34, 35, 36, 44), even in IGF-I-supplemented animals (36). However, once a female reached an age when first ovulation would be expected, estradiol replacement decreased serum IGF-I yet continued to increase IGFBP-3, again even in IGF-I-supplemented animals. These data in monkeys are supported by observations that estrogen-based oral contraceptives suppress IGF-I levels in young women (45). The effects of estradiol replacement in older women are mixed, with oral doses typically suppressing (16, 17, 18, 46) and transdermal treatments either elevating or having no effect on IGF-I (16, 17, 46), a difference attributed to transdermal estrogen bypassing the enterohepatic circulation (6). However, the present data indicate that despite a nonoral mode of administration (sc diffusion), this change in estradiol action from a stimulatory to an inhibitory influence on IGF-I secretion occurs at the transition to adulthood, which is defined as first ovulation, and is not merely a function of old age.

The observation in adult females that even during IGF-I supplementation, estradiol elevates serum IGFBP-3 despite a suppression of serum IGF-I suggests that there is an age-dependent uncoupling in the regulation of IGF-I and IGFBP-3. As IGFBP-3 secretion is thought to be GH dependent (38), estradiol probably increases IGFBP-3 by enhanced GH secretion (1). In addition, the consistent elevation in serum IGFBP-3 by IGF-I supplementation supports observations in rats that IGF-I stimulates IGFBP-3 synthesis (42, 52) and secretion directly (36, 40) and slows IGFBP-3 degradation (53), suggesting that developmental increases and postpubertal declines in IGFBP-3 concentrations are the results of secretory fluctuations in both GH and IGF-I. These effects of IGF-I must be direct and not mediated through GH given IGF-I’s negative feedback activity on GH secretion (32). Although the facilitation of IGFBP-3 by IGF-I is quite controversial in humans (41), additional studies must clearly define the mechanisms by which IGF-I increases serum IGFBP-3 in female monkeys.

With respect to IGF-I regulation, estradiol is thought to stimulate IGF-I secretion via an augmentation of GH release (1, 44), an up-regulation of the hepatic GH receptor (37), and subsequent stimulation of hepatic IGF-I biosynthesis (54). However, a direct stimulation by estradiol of IGF-I synthesis in nonhepatic tissues (55) and secretion (56) has also been suggested. Nevertheless, it is not clear how these mechanisms which account for the facilitation of IGF-I by estradiol change with the transition to adulthood. The age-dependent decline in serum IGF-I may be associated with a decrease in GH secretion (6) and a deficit in hepatic GH receptor signal transduction (57), resulting in a reduced response in IGF-I secretion from GH stimulation (47). However, restoration of pulsatile GH secretion with continuous infusion of GHRH elevates serum IGF-I concentrations (58), suggesting that deficits in GH-induced IGF-I secretion may be due to an alteration in either GH pulse amplitude or frequency. In any event, the change that occurs during the transition from puberty into adulthood is specific to the regulation of IGF-I, as estradiol continues to elevate serum IGFBP-3. Furthermore, it must be emphasized that these data describe the regulation of peripheral IGF-I concentrations, which have implications for its effects on target tissues. As estradiol may still stimulate the paracrine or autocrine action of IGF-I locally in adult females (59), functional studies must define the mechanisms responsible for the change in estradiol regulation of IGF-I and how this change in peripheral IGF-I affects its endocrine actions.

As observed previously in humans (7), the molar ratio of IGF-I to IGFBP-3 increased through adolescence before declining into adulthood, and this was due to a proportionately greater change in IGF-I. Most IGF-I circulates bound to IGFBP-3 associated with an acid-labile subunit, and this complex acts as a slow release reservoir of IGF-I to target tissues (60). In the present study, the molar ratio was greatest during the juvenile and early adolescent phases, a period when monkeys are actively growing (35, 36), and was lowest in adults who have achieved full stature. Treatment with IGF-I elevated serum IGF-I more than that with IGFBP-3, resulting in an even greater molar ratio compared to that in nonsupplemented animals. As the age-dependent decrease in the molar ratio was still evident in supplemented animals, the data suggest that the IGF-I treatment used in the present study is additive to the endogenous production of IGF-I despite data suggesting that IGF-I may inhibit its own hepatic gene expression (42). Furthermore, the fact that IGFBP-3 is not increased to the same molar extent as IGF-I with IGF-I treatment supports the hypothesis that IGF-I is not the sole regulator of IGFBP-3 (36, 41) and that GH is also involved in IGFBP-3 production (38). Although estradiol increased the molar ratio only during early adolescence, the lower ratios in young and fully adult females reflect the suppression of IGF-I and facilitation of IGFBP-3 by estradiol occurring at this age. This age-dependent decrease in the molar ratio most likely affects the bioavailability of IGF-I, as a molar excess of the binding protein may actually limit IGF-I action (60). Although the shift to proportionately more IGFBP-3 may serve to "protect" adults from IGF-I action, functional studies are needed to fully understand how the bioavailability of IGF-I is affected by changes in the molar ratio between IGF-I and IGFBP-3 and what the physiological significance of these changes are as a function of age.

Baseline IGFBP-1 concentrations, before acute IGF-I administration, were highest in juveniles and lowest in adults, supporting normative data from humans that IGFBP-1 levels decrease throughout puberty (3, 4). Although serum IGFBP-1 is negatively correlated with IGF-I based on population-derived values (3), IGFBP-1 is regulated primarily by insulin (61), so that a developmental decrease is probably due to rising insulin secretion during puberty. Data from humans indicate that serum IGFBP-1 increases from the postpubertal-early adult period to senescence, an effect attributed to the inability of insulin to suppress IGFBP-1 in older individuals (62). A further examination of serum IGFBP-1 revealed that estradiol replacement significantly elevated serum IGFBP-1 in adult, but not adolescent, females, abolishing the age difference observed during no estradiol replacement. Estradiol reverses the inhibitory action of insulin on serum IGFBP-1 in young women (63), possibly due to an improvement in insulin resistance, as shown in older females (64). Although the precise mechanism for this effect awaits experimental verification, it is interesting to note that estradiol functions to increase two of the major binding proteins for IGF-I in adult animals.

The sampling frequency used in the present study was less than optimal to fully characterize spontaneous GH secretion as well as well as the negative feedback response to IGF-I but, when evaluated in conjunction with the change in serum GH to GHRH administration, the analysis indicated that GH concentrations are lower in older females and that these reduced levels may be due to enhanced sensitivity to IGF-I negative feedback. Chronic IGF-I infusion dampened the response to GHRH in adult as well as young adult females, but not in juvenile females. This age-dependent effect was also seen during acute IGF-I treatment, as serum GH was briefly suppressed in juveniles, but was maximally suppressed in adults throughout the sampling period. Importantly, however, estradiol replacement tended to elevate spontaneous GH concentrations in IGF-I-treated monkeys and significantly increased the response of serum GH to GHRH in adult, IGF-I-supplemented females. As neither IGF-I nor estradiol had an effect on the response to GHRH in juvenile animals, these data suggest that the sensitivity to IGF-I negative feedback suppression of GH secretion is increased during the transition to adulthood, but that this inhibition can be reversed by estradiol replacement.

The response to exogenous GHRH is affected by inhibitory effects on GHRH neurons (65) and increased somatostatin tone coincident with GHRH administration (12, 66), resulting in inadequate priming of the pituitary (67). These mechanisms may be exacerbated in older individuals, accounting for the observed deficits in GHRH responsiveness (11). Aging has been characterized by diminished GHRH secretion (23, 24) and reduced GHRH mRNA (25) as well as an increased release of somatostatin (68) and a heightened response to somatostatin inhibition (69). IGF-I not only decreases hypothalamic GHRH mRNA (30) and release (70), but increases somatostatin biosynthesis (71, 72). In addition to these hypothalamic effects, IGF-I acts directly on somatotrophs to decrease GH gene transcription and secretion (73). Consequently, it is possible that these neuroendocrine mechanisms mediating IGF-I negative feedback are exacerbated with aging, producing a hypersensitivity to IGF-I inhibition of GH secretion. Although an increased sensitivity to IGF-I negative feedback is not evident in aged men and women (32), the present data indicate that IGF-I becomes more effective in suppressing GH secretion when comparing juvenile to young and fully adult females. It is possible that the further decrements in GH secretion observed in aged individuals (10, 32) are due to factors in addition to IGF-I negative feedback. As GH can inhibit its own secretion (74) through a suppression of GHRH mRNA (30) and an increase in somatostatin secretion (74), it is possible that despite a decline in serum GH, GH negative feedback on GHRH and somatostatin neurons may also be enhanced with advancing age.

The restored response in serum GH to GHRH in older, IGF-I-supplemented monkeys after estradiol replacement is probably due to an effect on somatostatin or GHRH neurons. Estrogen receptors are not found on somatostatin neurons (75), so any effects must be mediated through interneuron populations. As gonadal steroids increase somatostatin gene expression in adults (76), estradiol may augment GH secretion by increasing somatostatin release, sensitizing the pituitary to GHRH stimulation (12). On the other hand, GHRH neurons in the arcuate nucleus bind estradiol (20), and gonadal steroids increase GHRH gene expression through adulthood in rats (21). Consequently, estradiol may be acting at the GHRH neuron to increase gene expression and reestablish release of the peptide, priming the somatotroph for subsequent stimulation. The lack of an effect of estradiol on the response to GHRH in juvenile monkeys is similar to that observed in prepubertal humans (19), whereas the facilitory effect of estradiol on the response to GHRH in adult monkeys is analogous to that seen in premenopausal women (26). These data suggest that estradiol is capable of restoring GH secretion under conditions where inhibition of the GH axis is increased. However, estradiol replacement does not enhance the response to GHRH in postmenopausal women (18, 27), suggesting that extreme deficits in GH secretion in aged individuals cannot be restored by gonadal steroid stimulation. Additional studies are needed to investigate the age-dependent changes in sensitivity to somatostatin and GHRH and how these may be modified by varying doses of estradiol to further define how GH is regulated differentially during the transition from puberty to adulthood and senescence.


   Acknowledgments
 
The invaluable technical assistance of M. Lindsley, K. Chikazawa, and S. Lackey is greatly appreciated. Reagents for the IGF-I, GH, and LH assays were generous gifts from the National Hormone Pituitary Program, NIDDK, USDA, NICHHD, and Dr. A. F. Parlow, University of California-Los Angeles. Recombinant human IGF-I was a generous gift from Genentech (South San Francisco, CA).


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

Received November 19, 1997.

Revised February 23, 1998.

Accepted March 2, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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