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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0173
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 3897-3903
Copyright © 2005 by The Endocrine Society

Comparison of the Metabolic Effects of Raloxifene and Oral Estrogen in Postmenopausal and Growth Hormone-Deficient Women

James Gibney, Gudmundur Johannsson, Kin-Chuen Leung and Ken K. Y. Ho

Pituitary Research Unit, Garvan Institute of Medical Research (J.G., G.J., K.-C.L., K.K.Y.H.), and Department of Endocrinology (K.K.Y.H.), St. Vincent’s Hospital, Sydney, New South Wales 2010, Australia

Address all correspondence and requests for reprints to: Dr. Ken K. Y. Ho, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia. E-mail: k.ho{at}garvan.org.au.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The endocrine and metabolic functions of the liver are affected by estrogen. Oral estrogen reduces IGF-I and suppresses fat oxidation despite augmenting GH secretion. The aim of this study was to determine whether selective estrogen receptor modulators display similar effects and whether these effects are magnified in GH-deficient (GHD) women because of the loss of GH feedback.

Design: This was an open-label, randomized, two-period, crossover study comparing treatment (raloxifene vs. estradiol) and group (normal vs. GHD).

Setting: The setting of this study was a clinical research unit.

Participants: Twelve postmenopausal women and 12 women with hypopituitarism participated in this study.

Intervention: Two 4-wk treatments with 17ß-estradiol (E2; 2 mg, followed by 4 mg) or raloxifene (60 mg, followed by 120 mg) were given, crossing over to the alternate treatment after a 4-wk washout period.

Outcome Measures: Endocrine [GH, IGF-I, IGF-binding protein-3 (IGFBP-3), GH-binding protein, and SHBG] and metabolic (fat oxidation) end points were used as outcome measures.

Results: E2 reduced serum IGF-I levels in a dose-dependent manner in both groups, with effects greater (P < 0.05) than raloxifene. Raloxifene reduced IGF-I levels in the GHD group (P < 0.001), but not in the postmenopausal group. E2 reduced (P < 0.05), and raloxifene increased (P < 0.05), IGFBP-3 levels in both groups. E2, but not raloxifene, increased GH (P < 0.05) in postmenopausal women. The effects of E2 and raloxifene on IGF-I, IGFBP-3, IGF-I/IGFBP-3 molar ratio, GH-binding protein, and SHBG were significantly different (P < 0.05). E2 and raloxifene reduced (P < 0.05) fat oxidation equally in GHD, whereas the decrease in postmenopausal women was not significant.

Conclusion: E2 and raloxifene exert different hepatic endocrine, but not lipid oxidative, effects. The greater effects seen in GHD women may be explained by the loss of endogenous GH feedback.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THROUGH A FIRST-PASS hepatic effect, orally administered estrogen reduces circulating IGF-I (1, 2), increases GH-binding protein (GHBP) (2), and reduces fat oxidation (3). These effects are apparent in both postmenopausal GH-replete women (3) and hypogonadal GH-deficient (GHD) women (4) and provide a mechanistic explanation for the observed reduction in lean body mass and increase in fat mass that occur during treatment with oral estrogen (3).

The nonsteroidal benzothiopene, raloxifene, is a selective estrogen receptor modulator (SERM) with tissue-specific estrogen agonistic and antagonistic activities (5). Raloxifene exerts agonistic effects on bone and antagonistic effects on breast and uterus (5). Differential effects on plasma lipid profile and coagulation factors (6) suggest that the hepatic effects of raloxifene are not identical with those of estrogen. Although recent studies have demonstrated that raloxifene reduces IGF-I in healthy postmenopausal (7, 8), type 2 diabetic (9), and acromegalic (10) women, little is known about whether it affects hepatic metabolism, or how the effects of raloxifene on the GH/IGF-I system compare with those of oral estrogen.

To address these questions, we performed a study to compare the hepatic endocrine and metabolic effects of oral estrogen and raloxifene. Resting energy expenditure and substrate oxidation were measured in the fasting state and after a mixed meal, under which conditions we have previously demonstrated that the effects of oral estrogen are most reproducible (3). To investigate whether any differences in the effects of raloxifene and oral estrogen could be explained by changes in GH secretory status, identical studies were carried out in GHD patients and GH-sufficient postmenopausal women.


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

Twelve hypopituitary GHD women with hypogonadism were recruited from the Endocrine Outpatient Clinic, St. Vincent’s Hospital (Sydney, Australia). GH deficiency (GHD) was confirmed by a peak GH response of less than 3 ng/ml during an insulin tolerance test (11). None of the patients was receiving GH replacement or had received GH within 1 yr before commencement of the study. The duration of hypopituitarism was at least 1 yr. All were receiving stable hormone replacement for other deficiencies. Twelve normal postmenopausal subjects were recruited from the general population, all of whom had cessation of menses for at least 12 months, with postmenopausal status confirmed by elevated gonadotropins and low estradiol levels. Subjects who were receiving estrogen replacement therapy had this discontinued at least 2 months before entry into the study. All were in good health and not taking other medications. The clinical characteristics of both groups are shown in Table 1Go. The research ethics committee of St. Vincent’s Hospital approved the study. All subjects gave written informed consent.


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  		TABLE 1. Clinical characteristics of GHD and postmenopausal subjects

 
Study design

This was an open-label, randomized, crossover design, allowing for differences in treatment effect (estrogen and raloxifene) and different responses between groups (GHD and postmenopausal) to be compared (Fig. 1Go). Each subject was randomized to oral 17ß-estradiol (E2; Zumenon, Solvay, Sydney; 2 mg/d for 4 wk, followed by 4 mg/d for 4 wk) or raloxifene (Evista, Eli Lilly & Co., Sydney, Australia; 60 mg/d for 4 wk, followed by 120 mg/d for 4 wk). After a 4-wk washout phase, the subjects were crossed over to the alternate treatment. Medroxyprogesterone acetate (10 mg daily) was administered for 10 d immediately after each 4-wk cycle of estrogen treatment to induce withdrawal bleeding. At baseline and at the end of the study (d 28) in each treatment phase, blood was drawn for measurement of GH, IGF-I, IGF-binding protein-3 (IGFBP-3), SHBG, and GHBP, and indirect calorimetry was performed. All investigations were carried out at 0800 h after an overnight fast.



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  		FIG. 1. Women with severe GHD (n = 12) and postmenopausal (n = 12) women were randomized to receive two 4-wk treatment periods with E2 (2 mg, followed by 4 mg; group A) and raloxifene (Ral; 60 mg, followed by 120 mg; group B). After a 4-wk washout period, the women were crossed over to the alternate treatment. Medroxyprogesterone acetate (MPA) was administered for 10 d after each 4-wk E2 treatment period.

 
Study techniques

Energy expenditure and substrate oxidation were measured by indirect calorimetry in the fasting and postprandial states, using the Deltatrac Metabolic Monitor (Datex Instrumentarium Corp., Helsinki, Finland) as previously described (3). A standardized mixed meal (334 ml containing 500 kcal, made up of 14% protein, 31.5% fat, and 54.5% carbohydrate; Ensure Plus, Ross Laboratories, Columbus, OH) was then administered, and indirect calorimetry was performed during the 30- to 60-min and 90- to 120-min periods after the nutrient load.

Energy expenditure and substrate oxidation were calculated from the following equations: energy expenditure = 3.91 VO2 + 1.10 VCO2 – 3.34 Nu; fat oxidation = 1.67 VO2 – 1.67 VCO2 – 3.34 Nu; and carbohydrate oxidation = 4.55 VCO2 – 3.21 VO2 – 1.92 Nu (12). Carbohydrate and lipid oxidation are expressed as grams per minute. VO2 represents oxygen consumption, and VCO2 represents carbon dioxide production in liters per minute. Nu represents urinary urea nitrogen in grams per minute. This value was estimated based on body weight, as previously described (12).

Laboratory analysis

GH was measured by ELISA, as previously described (13). The ELISA has a sensitivity of 0.001 µg/liter, intraassay coefficients of variation (CV) of 6% and 8% (n = 14), and interassay CV of 10 and 9% (n = 10) at 0.08 and 2 µg/liter GH, respectively. IGF-I was measured by RIA after acid-ethanol extraction using a recombinant human IGF-I standard. The intra- and interassay CV for IGF-I were 8.2% and 13.0%, respectively. Serum IGFBP-3 was measured by RIA (Bioclone, Sydney, Australia). The intraassay CV were 6.0 and 2.6% at 1.6 and 7.3 µg/ml, respectively. The interassay CV were 6.9 and 4.9% at 1.4 and 6.8 µg/ml, respectively. GHBP was measured by a ligand immunofunctional assay, as previously described (14), and the intra- and interassay CV were 9.2 and 14.4%, respectively. SHBG was measured by a commercial kit (Immulite 2000, Diagnostic Products Corp., Los Angeles, CA); the intraassay CV were 2.5 and 5.3% at 21 and 80 mmol/liter, respectively.

Statistics

Descriptive statistical analysis is presented as the mean ± SEM. Within-group treatment effects were analyzed using Friedman’s ANOVA for repeated measurements, followed by Wilcoxon’s matched pairs signed rank-sum test if significance was obtained. Between-group effects were analyzed using the Mann-Whitney U test. Statistical significance was set at an {alpha} level of 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The GHD women were younger than the postmenopausal women (43.9 ± 3.9 vs. 60.5 ± 2.3 yr; P < 0.001), but their body mass indexes were similar (30.4 ± 2.0 vs. 27.6 ± 1.0 kg/m2; Table 1Go). Treatment was well tolerated, and the response was not influenced by the sequence of administration of E2 and raloxifene.

IGF-I, IGFBP-3, and GH

The mean IGF-I concentration in GHD women was significantly lower (P < 0.05) than that in postmenopausal women throughout the study (Fig. 2Go). In GHD women, raloxifene and E2 reduced serum IGF-I levels compared with baseline in a dose-dependent manner. In postmenopausal women, E2 reduced IGF-I in a dose-dependent manner, whereas the fall after raloxifene treatment was not statistically significant. A 2-mg dose of E2 produced a serum IGF-I level lower than that after treatment with 120 mg raloxifene. Thus, the reduction in IGF-I induced by raloxifene was significant in GHD women only, whereas that with E2 was significant in both groups.



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  		FIG. 2. Serum IGF-I concentrations in morning samples from GHD and postmenopausal women treated with E2 or raloxifene (Ral) as described in Fig. 1Go. *, P < 0.05; **, P < 0.01; ***, P < 0.001 (compared with baseline. Serum IGF-I levels were lower in the GHD group at all time points.

 
Mean IGFBP-3 levels were not significantly different between the two groups at baseline (Fig. 3Go). In GHD women, IGFBP-3 rose significantly during raloxifene treatment and fell slightly during E2 treatment, although the difference did not reach statistical significance compared with baseline. However, mean levels were significantly lower during E2 treatment (P < 0.05) compared with those during raloxifene treatment. In postmenopausal women, serum IGFBP-3 levels increased significantly (P < 0.05) with both 60- and 120-mg doses of raloxifene. The levels observed during E2 treatment were significantly lower (P < 0.05) than those with raloxifene. Thus, raloxifene increased IGFBP-3 significantly in both groups.



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  		FIG. 3. Serum IGFBP-3 concentration in morning samples from GHD and postmenopausal women treated with E2 or raloxifene as described in Fig. 1Go. *, P < 0.05 (compared with baseline). §, P < 0.05 (compared with 60 and 120 mg raloxifene). Serum IGFBP-3 levels were lower in the GHD group only after the two doses of raloxifene.

 
The calculated molar ratio of IGF-I/IGFBP-3 fell to a similar degree with both doses of raloxifene and E2 in the two groups (Table 2Go). In response to 120 mg raloxifene and 4 mg E2, the mean molar ratio fell by 32% and 26%, respectively, in the GHD group and by 27% and 20%, respectively, in the postmenopausal group. The molar ratio of IGF-I/IGFBP-3 was lower in the GHD women throughout the study (P < 0.05). There was a significant correlation between changes in serum IGF-I and IGFBP-3 levels produced by 120 mg raloxifene in both GHD (r = 0.58; P < 0.04) and postmenopausal (r = 0.59; P < 0.04) women.


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  		TABLE 2. Molar ratio between serum IGF-I and IGFBP-3, serum concentration of GHBP, and SHBG in women with severe GHD (n = 12) and postmenopausal (n = 12) women randomized to receive two 4-wk treatment periods with E2 (2 mg, followed by 4 mg) and raloxifene (Ral; 60 mg, followed by 120 mg)

 
Fasting GH levels were significantly lower (P < 0.001) in the GHD group (Fig. 4Go). In GHD women, neither raloxifene nor E2 treatment affected the fasting serum GH concentration. In postmenopausal women, the lower dose of raloxifene did not increase the serum GH concentration, whereas a strong trend toward an increase was noted with the higher dose (P = 0.08). Both doses of E2 increased mean fasting GH in a dose-dependent manner. In postmenopausal women, mean GH was stimulated by E2 treatment, but only weakly by raloxifene.



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  		FIG. 4. Serum GH concentrations in a fasting morning sample from GHD and postmenopausal women treated with E2 or raloxifene as described in Fig. 1Go. *, P < 0.05 (compared with baseline). {dagger}, P < 0.05 (compared with GHD women).

 
GHBP and SHBG (Table 2Go)

The mean baseline GHBP concentration in GHD women was significantly higher than that in postmenopausal women. In the GHD group, serum GHBP was unaffected by raloxifene treatment, but was increased significantly by E2 in a dose-dependent manner. In postmenopausal women, raloxifene treatment did not significantly affect, whereas E2 treatment increased, GHBP levels.

The response pattern for serum SHBG was similar to that for GHBP. In both groups, SHBG was not significantly affected by raloxifene, but increased dose-dependently with E2 treatment. The increase in SHBG was greater than that in GHBP during E2 treatment.

Energy expenditure and fat oxidation (Table 3Go)

Resting energy expenditure was not different between the groups and was not affected by either raloxifene or E2 treatment. Fat oxidation in the fasting state was not significantly different between the two groups and was not influenced by either treatment.


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  		TABLE 3. Fat oxidation in women with severe GHD (n = 12) and postmenopausal women (n = 12) randomized to receive two 4-wk treatment periods with E2 (2 mg, followed by 4 mg) and raloxifene (Ral; 60 mg, followed by 120 mg)

 
Ingestion of the standardized meal acutely suppressed fat oxidation during each treatment phase. In the GHD group, raloxifene treatment resulted in a greater suppression of fat oxidation during the first hour after ingestion. A greater suppression of fat oxidation also occurred during E2 treatment. The suppression was neither dose dependent nor different between raloxifene and E2 treatments. In postmenopausal women, a trend toward a reduction in postprandial fat oxidation occurred with both treatments, although the changes did not reach statistical significance (P = 0.06). In summary, raloxifene and E2 significantly suppressed postprandial fat oxidation equally in GHD women, whereas the effects in postmenopausal women were modest and not statistically significant (Table 4Go).


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  		TABLE 4. Summary of the effects of E2 and raloxifene (Ral) in GHD and postmenopausal subjects

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This randomized, open-label, crossover study demonstrates that orally administered E2 and raloxifene exert differential hepatic endocrine and metabolic effects, and that these effects differ in GHD compared with healthy postmenopausal women. In GHD and postmenopausal women, both compounds reduced serum IGF-I, with E2 having a greater effect. The compounds induced opposite effects on IGFBP-3, with raloxifene increasing and E2 reducing the levels in blood. Both raloxifene and E2 suppressed postprandial fat oxidation equally in GHD women. The effects of both treatments on reducing IGF-I and suppressing fat oxidation were greater in GHD than in postmenopausal women.

The influence of estrogens on the GH/IGF-I axis is dose dependent and is dictated by effects exerted on the liver (2, 4, 15). We have previously reported that different estrogen formulations cause an equal dissociation of the GH/IGF-I axis when administered by the oral route (15). The extent of IGF-I suppression was related to the extent of GH elevation and stimulation of estrogen-sensitive hepatic proteins, such as SHBG and GHBP, suggesting that IGF-I suppression is the result of a first-pass hepatic effect (15). Recent evidence suggests that raloxifene also reduces IGF-I in certain clinical settings. Raloxifene has been shown to reduce IGF-I in healthy postmenopausal women (7, 8), women with breast cancer (16), and men and women with acromegaly (17, 18). In the current study, raloxifene significantly reduced IGF-I only in GHD women. E2 reduced IGF-I in both GHD and postmenopausal women and increased GH secretion in postmenopausal women. These findings suggest that raloxifene exerts a relatively weak effect on IGF-I, which was unmasked only in a GHD state.

In GHD and postmenopausal women, SHBG and GHBP levels did not change during treatment with raloxifene. The neutral effects of raloxifene on GHBP have not previously been reported. GHBP corresponds to the extracellular domain of the GH receptor, and although it remains unproven, it is believed that circulating GHBP reflects tissue GH receptor status. The biological relevance of the effect of estrogen to increase GHBP is unknown; therefore, the significance of the differential effects of E2 and raloxifene on GHBP is not clear.

This is the first report of the effect of raloxifene on the oxidative metabolism of fat. Previous studies in postmenopausal women (8, 19, 20, 21, 22) and in women with type 2 diabetes (9) have demonstrated that raloxifene exerts no effect on carbohydrate metabolism (9, 10, 21, 22) or insulin sensitivity (19, 20). In the current study, raloxifene significantly suppressed fat oxidation. The effect was similar in extent to that of E2 and reached statistical significance only in GHD women. We previously reported that oral, but not transdermal, estrogen administration suppressed fat oxidation in a dose-dependent manner in hypogonadal women using synthetic and conjugated estrogens (3). The inability to detect a significant fall in postmenopausal women in the present study may arise from the smaller sample size and the use of a less potent estrogen formulation. Because GH stimulates fat oxidation (23), the absence of compensatory stimulation renders GHD women more susceptible to the suppressive effects of raloxifene and E2 on hepatic fat oxidation.

Unlike their similar effects on IGF-I, raloxifene and E2 exerted divergent effects on IGFBP-3. Duschek et al. (7) recently reported that raloxifene increased IGFBP-3 in postmenopausal women, but conjugated equine estrogen had no effect. IGF-I circulates primarily bound to IGFBP-3 and acid-labile subunit as a ternary complex, with only a small fraction unbound. IGF-I and IGFBP-3 are produced from different cell types in the liver, with the former and acid-labile subunit synthesized in hepatocytes, and the latter in Kupffer cells (24, 25). It has been shown that IGFBP-3 serves as a passenger protein in the IGF ternary complex, with any unbound IGFBP-3 rapidly cleared from the circulation, so its level in blood is normally determined indirectly by complex formation to IGF (26). The increase in IGFBP-3 after raloxifene treatment suggests that its synthesis was stimulated. The mechanism(s) behind this is unknown, but warrants additional study.

The endocrine and metabolic effects of E2 and raloxifene observed in this study have implications for the maintenance of body composition and functional capacity in both healthy postmenopausal and GHD subjects. Reduced IGF-I during treatment with oral estrogen is associated with reduced lean body mass in postmenopausal women (3) and reduced protein synthesis in GHD subjects (4). Although the effect of raloxifene in lowering total IGF-I was modest compared with that of E2, its effect in reducing the IGF-I/IGFBP-3 ratio was at least as marked because of the concomitant increase in IGFBP-3. This suggests that raloxifene could reduce the bioavailability of IGF-I or the circulating free IGF-I levels to a similar degree as E2. Higher circulating IGF-I is associated with an increased risk of the development of breast (27), prostate (28), and colon (29) cancers. The association was considerably stronger after adjusting for IGFBP-3 levels; the relative risk was highest in subjects with high and lowest in those with low IGF-I/IGFBP-3 ratios. A low ratio may confer an antitumorigenic effect, consistent with the observation that SERMs protect against breast cancer recurrence and progression (30, 31). If a low IGF-I/IGFBP-3 ratio translates to reduced anabolic activity, the implications may be of particular importance for GHD women, who have reduced muscle mass, strength, and exercise tolerance.

The results of the current study also suggest that raloxifene is unlikely to impart any benefit on fat metabolism in either postmenopausal or GHD women. We have previously demonstrated in postmenopausal women that daily administration of 1.25 mg conjugated equine estrogens reduced fat oxidation and increased total body fat by 5% over a 6-month period compared with transdermal estrogen (3). Similarly, we have shown that the effect of oral estrogen in reducing fat oxidation in GHD women does not occur with transdermal estrogen (4). Thus, the current body of evidence suggests that in terms of effects on fat metabolism, transdermal estrogen confers an advantage over both oral estrogen and raloxifene.

The molecular mechanisms underlying the effects of estrogen and estrogen-like compounds to influence GH signaling have recently been elucidated. After binding to and dimerization of its receptor, GH increases IGF-I production through stimulation of the cytokine-signaling (Janus kinase-signal transducer and activator of transcription) pathway (32). Down-regulation of this pathway is mediated through a recently identified family of molecules, the suppressors of cytokine signaling (SOCS). We have shown that in a number of cell lines, including one derived from hepatocytes, estrogen increases SOCS-2 mRNA, and that in cells devoid of SOCS-2, the inhibitory effects of estrogen on GH signaling were abolished (33). These findings provide convincing evidence that estrogen inhibition of GH signaling is mediated by SOCS-2. How other sex steroids, including testosterone and SERMs, influence these pathways is not known, but clearly merits additional study.

In summary, in the doses used, raloxifene exerted less potent, but also different, effects on components of the GH/IGF-I axis compared with E2, whereas effects on hepatic fat oxidation were similar. Unlike E2, Ral increased IGFBP-3, an effect that may reduce the bioavailability of free IGF-I and its anabolic action. We conclude that raloxifene is unlikely to have a metabolic advantage over oral E2 in relation to its effects on fat and lean body mass in GHD and postmenopausal women.


   Acknowledgments
 
We thank Bronwyn Heinrich and Maria Males for excellent clinical assistance.


   Footnotes
 
This work was supported by Lilly Australia and the National Health and Medical Research Council of Australia.

First Published Online April 26, 2005

Abbreviations: CV, Coefficient(s) of variation; E2, 17ß-estradiol; GHD, GH-deficient or GH deficiency; GHBP, GH-binding protein; IGFBP, IGF-binding protein; SERM, selective estrogen receptor modulator; SOCS, suppressor of cytokine signaling.

Received January 26, 2005.

Accepted April 19, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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