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Department of Endocrinology, Christie Hospital, Manchester, United Kingdom M20 4BX
Address all correspondence and requests for reprints to: Prof. S. M. Shalet, Department of Endocrinology, Christie Hospital, Manchester, United Kingdom M20 4BX. E-mail: stephen.m.shalet{at}man.ac.uk.
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Abstract |
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Introduction |
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Evidence from patients with GH deficiency (GHD) also suggests that gender influences the relationship between serum GH and IGF-I. Despite use of the same cut-off to provocative testing, untreated GHD females have significantly lower serum IGF-I levels and require significantly higher doses of GH replacement to maintain equivalent serum IGF-I values as males of similar GH status (6).
Estrogen is one likely explanation for the gender difference, as evidenced by a 2-fold increase in serum GH at the mid portion of the menstrual cycle without a concomitant rise in serum IGF-I (7, 8). Furthermore, oral estrogen therapy increases GH secretion and decreases IGF-I levels in postmenopausal women (9, 10, 11, 12, 13, 14). This suggests that oral estrogen therapy inhibits GH-stimulated IGF-I secretion, thus resulting in diminished feedback at the hypothalamic-pituitary axis and, hence, increased GH levels.
A number of researchers have examined the impact of transdermal estrogen on the somatotropic axis, but have described disparate results, with IGF-I being variably reduced (12), unaffected (10, 13), or increased (11, 15) by transdermal estrogen.
A potential explanation for this lack of agreement may be that the type of estrogen used in the oral and transdermal preparations (11, 13, 16, 17) varied. As different formulations of oral estrogen are known to cause variable degrees of IGF-I suppression (9), it is inappropriate to compare, for example, oral ethinyl estradiol with transdermal estradiol valerate, as the former preparation, at least when administered orally, is a more potent suppressor of IGF-I than the latter. Another confounding variable is that doses of oral and transdermal estrogen may not have been equivalent (12, 18, 19).
We have attempted to overcome these difficulties by using the same estrogen (estradiol) for both transdermal and oral estrogen and by using two doses of transdermal estradiol: 50 µg, a dose thought to mimic levels of estrogen in the follicular phase of the menstrual cycle, and 200 µg, a supraphysiological dose. Furthermore, using estradiol rather than conjugated equine estrogen or ethinyl estradiol allowed us to measure circulating estradiol and estrone levels, thus enabling us to compare doses of estrogen used in the oral and transdermal preparations.
The IGF-I generation test has been used for many years to assess GH responsiveness in children with short stature (20) and more recently has been used in adults (21, 22, 23). Potentially, assessment of the acute IGF-I response to exogenous GH amplifies subtle abnormalities in GH responsiveness not detected by study of baseline values alone. Furthermore, by examining the IGF-I response to a supraphysiological dose of GH, the potentially confounding influence of changes in endogenous GH secretion is removed.
We have designed this study to examine the acute responses of IGF-I, IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) to GH.
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Subjects and Methods |
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The local ethical committee approved the study, and the subjects gave written informed consent.
All women were at least 12 months postmenopausal and had not received exogenous estrogen for at least 8 wk before taking part in the study. None was receiving any drugs known to affect the GH/IGF-I axis.
Assays
Serum IGF-I. Serum IGF-I was measured by an in-house RIA after acid-alcohol extraction. The intraassay coefficients of variation for mean IGF-I concentrations of 45, 243, and 698 µg/liter were 9.0%, 6.5%, and 4.7%, respectively. The sensitivity of the assay was 13 µg/liter. The interassay coefficients of variation for mean IGF-I concentrations of 75, 196, and 698 µg/liter were 10.5, 10.1, and 5.1%, respectively.
Serum IGFBP-3. Serum IGFBP-3 was measured by an immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX). The intraassay coefficients of variation for mean IGFBP-3 concentrations of 1.0, 2.2, and 9.8 mg/liter were 6.1, 4.1, and 4.4%, respectively. The sensitivity of the assay was 0.5 µg/liter. The interassay coefficients of variation for mean IGFBP-3 concentrations of 0.9, 3.5, and 11.0 mg/liter were 9.0, 4.6, and 3.8%, respectively.
Serum ALS. Serum ALS was measured by an ELISA (Diagnostic Systems Laboratories). The intraassay coefficients of variation for mean ALS concentrations of 1.65, 7.72, and 29.17 mg/liter were 6.1, 7.5, and 3.8%, respectively. The sensitivity of the assay was 0.7 µg/liter. The interassay coefficients of variation for mean ALS concentrations of 2.22, 7.90, and 30.13 mg/liter were 8.6, 2.8, and 8.9%, respectively.
Serum estradiol. Serum estradiol was measured by RIA (Diagnostic Systems Laboratories, Houston, TX). The intraassay coefficients of variation for mean estradiol concentrations of 19.6, 92.1, and 342.6 pmol/liter were 8.9%, 6.5%, and 6.9%, respectively. The sensitivity of the assay was 8.1 pmol/liter (to convert to picograms per milliliter, divide by 3.7). The cross-reactivity with estrone was 2.4%.
Serum estrone. Serum estrone was measured by RIA with double-antibody separation of bound and free fractions (Diagnostic Systems Laboratories). The intraassay coefficients of variation for mean estrone concentrations of 376.3, 1825.6, and 3474.3 pmol/liter were 5.6, 9.4, and 4.4%, respectively. The sensitivity of the assay was 4.4 pmol/liter (to convert to picograms per milliliter, divide by 3.7). The cross-reactivity with estradiol was 1%.
Statistics
Data are presented as the median, with the interquartile range in parentheses, unless otherwise stated. Statistical analyses were performed with SigmaStat software (SigmaStat for Windows, version 1.0, Jandel Corp., San Rafael, CA). The Friedman repeated measures ANOVA on ranks was used to examine changes in the variables after administration of the different estrogen preparations. If a statistically significant difference was found, the Student-Newman-Keuls test (nonparametric version) was performed. Correlations were sought by calculating Pearson’s linear correlation coefficient. Forward stepwise multiple linear regression analysis was used to determine the strongest determinants of IGF-I SD score. Statistical significance was assumed for P < 0.05.
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Results |
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Serum estradiol and estrone levels during each study phase are given in Table 1
. Estradiol (P < 0.0001) and estrone (P < 0.0001) levels differed during the different treatment phases. Estradiol levels during oral estrogen therapy were approximately 3-fold higher than those during high dose transdermal estrogen therapy (P < 0.05). As expected, serum estrone levels were approximately 8-fold higher during oral estrogen therapy than during high dose transdermal estrogen therapy.
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Off estrogen treatment, serum IGF-I levels rose after GH administration from a baseline of 267.0 (195.5–322.5) µg/liter, to a peak of 528.0 (448.5–580.5) µg/liter at a median time of 24 h (Fig. 1). Both baseline (P < 0.01) and peak (P < 0.01) serum IGF-I levels differed during the various treatment phases.
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2 test, P < 0.01). Baseline serum IGF-I levels during high dose transdermal estrogen therapy [236.0 (184.5–300.0) µg/liter] were not significantly different from those off estrogen treatment; however, peak levels after GH stimulation [457.0 (420.0- 487.5) µg/liter] were lower than those achieved off estrogen treatment (P < 0.05).
IGF-I levels during low dose transdermal estrogen, both at baseline [234.0 (173.8–300.3) µg/liter] and the peak after GH administration [513.0 (455.3–546.3) µg/liter], were not significantly different from those off estrogen treatment.
The time to peak IGF-I levels differed between tests performed off estrogen treatment (24 h) and those performed during oral estrogen treatment (48 h; by 2 test, P < 0.01). A difference also existed between low dose transdermal estrogen (48 h) and tests performed off estrogen treatment (P < 0.05). The median time to the peak during high dose transdermal estrogen therapy was 24 h, and no significant difference was present compared with results off estrogen treatment. There was no significant difference in the timing of peak IGF-I levels among the different estrogen preparations.
Serum IGFBP-3
From a median level of 3.37 (2.86–3.66) mg/liter, serum IGFBP-3 peaked at a median of 4.23 (3.74–4.71) mg/liter 48 h after the administration of GH. Peak (P < 0.001), but not baseline, serum IGFBP-3 levels differed during the various treatment phases.
Although oral estrogen did not affect baseline levels of IGFBP-3 [3.03 (2.53–3.69) mg/liter], peak levels were significantly lower than those achieved off estrogen therapy [4.21 (3.34–4.34) mg/liter; P < 0.05].
High and low dose transdermal estrogen therapy affected IGFBP-3 in a similar pattern as oral estrogen; baseline values were not significantly different from values off estrogen treatment [2.91 (2.56–3.23) and 3.37 (2.95–3.57) mg/liter, respectively]. However, peak levels of IGFBP-3 were significantly lower during high dose transdermal estrogen therapy [3.84 (3.36–4.02) mg/liter; P < 0.05] and low dose transdermal estrogen [4.02 (3.66–4.36) mg/liter; P < 0.05] than values off estrogen treatment.
Serum ALS
Forty-eight hours after GH administration, ALS levels rose from a baseline of 10.10 (8.18–16.00) mg/liter to a peak of 14.0 (12.45–23.5) mg/liter off estrogen therapy. Both baseline (P < 0.05) and peak (P < 0.01) serum ALS levels differed during the various treatment phases.
Oral estrogen therapy affected neither the baseline nor the peak ALS level [9.00 (7.98–11.73) and 14.2 (12.85–17.5) mg/liter, respectively]. During high dose transdermal estrogen therapy, both baseline and peak ALS levels were lower than those off estrogen therapy [7.50 (6.88–9.45) mg/liter (P < 0.05) and 10.5 (9.90–13.6) mg/liter (P < 0.05), respectively]. Both baseline and peak ALS levels were also lower during low dose transdermal estrogen compared with values off estrogen treatment [7.00 (5.85–10.05) mg/liter (P < 0.05) and 12.0 (11.1–16.3) mg/liter (P < 0.05), respectively].
Determinants of baseline and peak levels of IGF-I
The correlation between baseline and peak levels of IGF-I and various potential determinants is presented in Table 2. Both baseline and peak IGF-I levels were negatively correlated with age and body mass index. Baseline IGF-I levels showed a nonsignificant trend to decline with increasing estrone levels, whereas peak IGF-I levels showed a nonsignificant trend to decline with increasing estradiol levels.
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). IGF-I was entered as the dependent variable, and age, body mass index, estradiol, and estrone levels were entered as potential determinants. In the case of peak IGF-I, baseline IGF-I was entered as an additional dependent variable. Age was the largest determinant of baseline IGF-I, contributing 44% to the variability in serum IGF-I levels. Estrone also significantly determined IGF-I at baseline, contributing 8% toward the variability. Peak IGF-I levels were only significantly influenced by IGF-I levels at baseline.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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It has been suggested that the effect of estrogen on responsiveness to GH is limited to that administered by the oral route. We demonstrated that transdermal estrogen also has a significant impact on responsiveness to GH despite achieving levels of circulating estradiol lower than those achieved by oral estrogen replacement. Oral estradiol reduced baseline and GH stimulated IGF-I levels, and GH stimulated IGFBP-3 levels. High dose transdermal estrogen did not affect basal levels of IGF-I or IGFBP-3, but reduced the responses of these GH-dependent peptides to GH stimulation. Low dose transdermal estrogen did not alter either baseline or peak IGF-I levels, but reduced the peak IGFBP-3 response to GH stimulation. Estradiol levels, assessed by an assay with low (2%) cross-reactivity with estrone, were lower during both transdermal estrogen preparations than during oral estrogen. Oral and high dose transdermal estrogen were associated with levels of estradiol above those normally found in the follicular phase of the menstrual cycle (70–250 pmol/liter).
Oral estrogen has been found to have a reasonably uniform effect on the somatotropic axis; however, different researchers have described variable results after transdermal estrogen. Some, notably Bellatoni et al. (13), found that transdermal estrogen caused no change in GH or IGF-I levels. However, Friend et al. (12) showed a decrease in serum IGF-I and a rise in the GH levels, similar to that seen with oral estrogen administration. There were, however, differences in design between these two studies that could explain the varied results. Firstly Friend et al. (12) used transdermal estrogen at high doses [two 100 µg 17ß-estradiol patches changed daily (Estraderm)], resulting in serum estradiol levels above 600 pmol/liter. Furthermore, this group used the same estrogen for their oral preparation (Estrace; 1 mg 17ß-estradiol daily). In contrast, Bellatoni and co-workers (13) studied a lower dose of transdermal estrogen (one 100 µg 17ß-estradiol patch) and used a different oral estrogen preparation [conjugated oral estrogen (Premarin), 1.25 mg daily], which is thought to have a greater effect on the GH/IGF-I axis than comparable doses of estradiol valerate (9) and, being equine-derived, prevented comparison of serum estradiol levels. Lastly, Slowinska-Srzednicka et al. (15) and Weissberger et al. (11) found a significant increase in IGF-I levels during treatment with 100 µg transdermal estradiol.
The effect of estrogen replacement on the response to GH replacement therapy provides further insight into the impact of estrogen on the somatotropic axis, particularly as the potential bias of changes in endogenous GH secretion is removed. Cook et al. (19) compared GH requirements in a group of GH-deficient women receiving unspecified preparations of oral estrogen with a mixed group containing some individuals receiving transdermal estrogen and some with normal endogenous estrogen secretion. The GH dose required to normalize IGF-I levels in women receiving oral estrogen was twice that required in the mixed group. More recently, Janssen et al. (18) switched GH- and LH-deficient women, who were already receiving stable GH replacement therapy, from oral estradiol (2 mg/d) to transdermal estradiol (50 µg/d). Serum IGF-I levels increased significantly after the switch from oral to transdermal estrogen therapy. However, levels of estradiol tended to be lower during transdermal compared with oral estrogen, leaving unanswered the question of the relative roles of route and dose in determining the increase in IGF-I observed with transdermal estrogen.
We have shown that transdermal estradiol does inhibit the IGF-I and IGFBP-3 responses to GH, although to a lesser extent than oral estrogen at the doses used in this study. However, levels of estradiol and estrone were considerably lower, even during the high dose transdermal phase, than those during oral estrogen treatment.
It is interesting to note that in contrast to IGF-I and IGFBP-3, both baseline and peak ALS levels were reduced only by transdermal estrogen and not by oral estrogen. These data contradict those reported by Kam et al. (24), who recently found parallel dose-dependent falls in serum IGF-I, IGFBP-3, and ALS after administration of various oral estrogen preparations to postmenopausal women, but no change in levels of IGFBP-3 and ALS during transdermal estrogen treatment.
Cook et al. (19) stated that women needing GH replacement therapy and exogenous estrogen should chose transdermal rather than oral estrogen replacement. Although a number of studies have examined the efficacy of transdermal estradiol, head to head comparative trials of oral vs. transdermal modes of administration remain few in number (25). Direct evidence of equivalent doses of transdermal and oral estrogen is scarce. In addition, data on doses of estrogen required to achieve and maintain peak bone mass in younger women are absent, and studies in older women may not necessarily translate to the younger women with hypogonadotropic hypogonadism, who may require estrogen replacement therapy for perhaps 20 yr. Thus, the optimal method of estrogen replacement for the young woman with hypogonadotropic hypogonadism is not yet clear.
In conclusion, it has been suggested that the effect of estrogen on responsiveness to GH is limited to that administered by the oral route. We have demonstrated that transdermal estrogen also has a significant impact on responsiveness to GH despite achieving levels of circulating estrogen lower than those achieved by oral estrogen replacement. The use of the IGF-I generation test allows more detailed examination of responsiveness to GH than basal levels of IGF-I alone. Our data also suggest that the low dose of transdermal estrogen used in earlier studies may explain the lack of effect of transdermal estrogen on the GH/IGF-I axis. The advice from the recent literature (19) that GH-deficient patients also receiving estrogen replacement therapy should be using transdermal estrogen is based on studies that used lower doses of transdermal estrogen than oral estrogen. These doses may not have the desired effect on bone mineral density, particularly in younger women. Hence, before such guidelines are widely accepted, further research is needed.
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Footnotes |
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Received January 7, 2003.
Accepted July 2, 2003.
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