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Articles

Sex Hormones and the Selective Estrogen Receptor Modulator Tamoxifen Modulate Weekly Body Weights and Food Intakes in Adolescent and Adult Rats¹

W. Jack Wallen^*,**, Michael P. Belanger and Carin Wittnich^*,,**2

Departments of ^* Physiology and Surgery, and ^** The Cardiovascular Sciences Collaborative Program, University of Toronto, Toronto, Canada M5S 1A8

²To whom correspondence and reprint requests should be addressed. E-mail: c.wittnich{at}utoronto.ca.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
This study documented the effect of changes in male and female sex hormones and the selective estrogen receptor modulator (SERM) tamoxifen on weight gain and food consumption of rats from puberty to adulthood, and assessed whether age at onset of treatment affected outcome. In Study 1, male and female WKY rats were either neutered or sham-operated before puberty, and a subgroup of neutered females underwent estrogen replacement (ERT) at the age of puberty. In Study 2, subgroups of neutered females received either ERT or tamoxifen beginning well into the postpuberty period. Weekly body weight and food consumption were assessed, and food consumption was normalized to metabolic weight (body weight^0.67). Neutering reduced the rate of weight gain in males (P < 0.05), but significantly increased it in females (P < 0.0001). ERT immediately reduced weight gain and prevented any further increase, resulting in weights below that of sham-operated females (P < 0.05). Tamoxifen prevented further weight gain and returned profiles to that of sham-operated females. Food consumption, normalized to metabolic weight, was similar in females and males, and both sexes showed a decrease through maturation to adulthood. Neutering decreased food consumption below that of sham-operated animals in both males and females (P < 0.05), and ERT returned it to sham levels. Despite the fact that tamoxifen had an effect on body weight similar to that of ERT, females receiving tamoxifen treatment consumed less food than both sham-operated and ERT females (P < 0.05). Weight gain is modulated by sex hormones in male and female rats, with both estrogen and tamoxifen exerting immediate effects in females, irrespective of the age at which treatment is initiated. Differences in food consumption do not appear to account for the effects of hormones and tamoxifen on body weight, suggesting that they exert a direct effect on overall body metabolism.

KEY WORDS: • gender • food consumption • growth • 17ß-estradiol • tamoxifen • rats

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Previous studies have shown that steroid hormones can influence the skeletal system and affect overall body mass and composition (1 ,2) . Appetite and food intake have also been found to be altered by steroid hormones. For example, estradiol has hypophagic effects, attributed to the direct effects of estradiol on the hypothalamus (3 ,4) . To date, the majority of studies into the effects of steroid hormones on body weight have been conducted in adult rats. Whether these hormone effects are affected by the age at which they are initiated is unknown. Earley and Leonard (5) documented changes in body weight and food consumption in intact and neutered male rats, which had been operated on as adults. However, the changes associated with steroid hormones could ultimately affect body weight changes throughout the developmental stage from adolescence to adulthood. Throughout maturation from adolescent to adult, the effect of gonadal steroids becomes more important as puberty is attained, and the levels of circulating steroids increase significantly. The literature lacks a systematic study comparing the effects of gonadal steroids on growth and food consumption throughout puberty into adulthood.

Selective estrogen receptor modulators (SERM),³ such as tamoxifen and nafoxidine, have also been shown to affect body growth (6 ,7) . Moon et al. (8) showed that tamoxifen decreased growth rates and prevented the decrease in bone density in female rats neutered at the age of sexual maturity. How tamoxifen alters the pattern of weight gain and food consumption in neutered females from puberty to adulthood has not been determined. This study was conducted to document the weekly profile of the effect of male and female sex hormones on weight gain and food intake of rats throughout the developmental stages, and to determine whether these effects are transitory or sustained. In addition, the effect of tamoxifen in neutered females was studied.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Age-matched male and female Wistar-Kyoto (WKY) rats were used for these studies (Charles River Laboratories, St. Constant, Canada). Animals were treated in accordance with the guidelines of the Canadian Council on Animal Care and the NIH. All animals were housed separately and were allowed free access to water. The rats consumed ad libitum a commercial nonpurified diet (Purina Rat Chow 5001; Ralston Purina Canada, Chomedy, Canada), with total energy (14.0 kJ/g) provided by protein (28%), fat (12%) and carbohydrates (60%).

Study 1.

At 17–21 d of age, female rats were randomly allocated to be either sham-operated (Sham, n = 9) or surgically neutered via bilateral ovariectomy (Neut, n = 17), leaving the uterus intact. A subgroup of these neutered females were given estrogen replacement therapy (ERT) with 17ß-estradiol (n = 9) for a total of 120 d of treatment, using slow-release pellets (1.7 mg estradiol, Innovative Research of America, Sarasota, FL) implanted subcutaneously every 60 d, beginning at 8 wk of age (9) . Sham rats underwent the identical implantation procedure but received no pellet. Overall, there were three groups of females, i.e., intact, neutered and neutered receiving ERT. Age-matched males were either surgically neutered via castration (Neut, n = 10) or were sham-operated (Sham, n = 8), for a total of two groups of males.

Study 2.

As in Study 1, female WKY rats were allocated to be either sham-operated (Sham, n = 7) or neutered (Neut, n = 13) at 17–21 d of age. A subgroup of these neutered females were given hormone replacement with the same dose of 17ß-estradiol used in Study 1 (ERT, n = 5) or tamoxifen (Tam, n = 4) using slow-release pellets (5 mg/pellet, Innovative Research of America) implanted subcutaneously every 60 d as in Study 1 (8) . ERT or tamoxifen treatment began at 12 wk of age in Study 2, 4 wk later than in Study 1. This is well into the postpuberty period in rats (10) . In rats surgically neutered or neutered and given hormone replacement using this protocol, plasma levels of 17ß-estradiol were undetectable in neutered females (<20 pmol/L), whereas intact females (85 ± 22 pmol/L) and neutered females receiving ERT (65 ± 15 pmol/L) had similar levels (P > 0.2). Neutered female rats receiving tamoxifen had undetectable (<20 pmol/L) plasma 17ß-estradiol. Plasma testosterone levels were 4 ± 2 nmol/L in intact males. Plasma 17ß-estradiol and testosterone were measured using commercial RIA kits (ICN Biomedicals, Costa Mesa, CA). All rats in both studies underwent the assessments detailed below.

Assessments.

Once each week, body weight (BW) of all rats from both studies was measured between the hours of 0900 and 1000 h. The amount of food consumed per week was determined by providing a measured quantity of food in excess of weekly requirements, and subtracting the amount remaining the next week. Food consumed per day per gram metabolic weight (BW^0.67) was also calculated (11 ,12) . The slope of the weekly growth curves for both male and female rats was determined for the weeks before initiation of ERT and for the weeks after treatment as well. At the appropriate age, rats were killed by an overdose of anesthetic (Inactin; Research Biochemicals International, Natick, MA). Completeness of neutering was confirmed post mortem by the absence of ovaries and testes. In all groups of females, the uterus was removed and weighed, and the ratio of uterus/BW (mg/g) was determined.

All data are expressed as means ± SEM. Data were analyzed using univariate repeated-measures ANOVA, with Duncan’s multiple range test post hoc. Student’s t test was used to analyze differences in slopes of growth curves between neutered and sham-operated males, and for neutered and sham-operated females before the initiation of treatment. One-way ANOVA with Scheffé’s test post hoc was used to analyze differences in slopes of post-treatment growth curves, uterus weight and uterus/BW ratio among females. All statistics were calculated using the Statistical Analysis System (version 7; SAS Institute, Cary, NC). For all tests, statistical significance was accepted at P < 0.05.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Study 1.

Uterus weight and uterus/BW ratios in neutered females were >90% smaller than those of sham-operated females and neutered females receiving ERT (Table 1 ). There was no significant difference in these variables between sham-operated females and neutered females receiving ERT.

View larger version (13K): [in this window] [in a new window]   Figure 1. Body weight of sham-operated (Sham) or neutered (Neut) male (A) and female (B) rats age 5–8 wk. Rats were operated on at 17–21 d. Values are means ± SEM, n = 9–17 (females) and 8–10 (males). Significantly different from sham-operated at the same age: aP < 0.05 (in some cases exceeding P < 0.0001). Significantly different from the previous week: bP < 0.0001.

View larger version (24K): [in this window] [in a new window]   Figure 2. Food consumption of sham-operated (Sham) or neutered (Neut) male (A) and female (B) rats, and food consumption normalized to metabolic weight of male (C) and female (D) rats, age 5–8 wk. Rats were operated on at 17–21 d. Values are means ± SEM, n = 9–17 (females) and 8–10 (males). Significantly different from sham-operated at the same age: aP < 0.05 (in some cases exceeding P < 0.0001). Significantly different from the previous week: bP < 0.0001.

Both sham-operated and neutered males showed increases in food consumption with age, although neutered males consumed 14% less than sham-operated males after wk 6 (Fig. 2 A, P < 0.0001). In contrast, both sham-operated and neutered females showed a much more blunted increase in food consumption, which was not significantly different after wk 6 (P = 0.45).

There was no difference in food consumption normalized to metabolic weight between sham-operated males and neutered males at any age (P = 0.15), although neutered males always consumed less. Food consumption in both groups of males increased with time, which tended to be blunted by neutering (P > 0.05; Fig. 2 C). There were no differences in normalized food consumption between sham-operated and neutered females at any age (P = 0.07), and the very modest rate of increase across time tended to be blunted by neutering (Fig. 2 D).

Growth curves for males and females for wk 8–22 are shown in Figures 3A and B, respectively. Week 8 values are included to enable comparison of pre-ERT data with post-ERT data. ERT of one group of neutered females was initiated immediately after assessment at wk 8. Both neutered and sham-operated males had rapid rates of growth until wk 12, followed by a slower but continued increase in weight (Fig. 3 A). Neutered males had 7% lower BW than sham-operated males throughout this period (P < 0.0001). A dramatic decrease in the rate of growth occurred after wk 12. For wk 8–12, similar slopes were found in sham-operated (19.3 ± 0.5 g/wk) and neutered (19.0 ± 0.8 g/wk, P = 0.7) males. From wk 13 to 22, the slopes of the growth curves of neutered (5.1 ± 0.2 g/wk) and sham-operated (6.0 ± 0.5 g/wk) males decreased by 73 and 69% vs. wk 8–12, respectively.

View larger version (16K): [in this window] [in a new window]   Figure 3. Body weight of sham-operated (Sham) or neutered (Neut) male (A) and female (B) rats age 8–22 wk. A subgroup of neutered females received 17ß-estradiol replacement (ERT) beginning at 8 wk. Rats were operated on at 17–21 d. Values are means ± SEM, n = 8–9 (females) and 8–10 (males). Significantly different from sham-operated at the same age: aP < 0.0001. Significantly different from ERT at the same age: bP < 0.001(in some cases exceeding P < 0.0001). Significantly different from the previous week: cP < 0.05 (in some cases exceeding P < 0.0001). Arrow indicates onset of 17ß-estradiol administration.

Neutered males consumed 10% less food than sham-operated males from 8 to 22 wk (P = 0.34) (Fig. 4A ). Neutered females receiving ERT consumed significantly less food than both sham-operated and neutered females throughout this period (Fig. 4 B). Interestingly, weekly food consumption in the neutered females receiving ERT showed a dramatic 17% reduction immediately after initiation of hormone replacement, which returned to more stable levels by wk 12 (P < 0.05). No such drop in food consumption occurred in sham-operated or neutered females, and both showed further increases by wk 10 (P < 0.05).

View larger version (35K): [in this window] [in a new window]   Figure 4. Food consumption of male (A) and female (B) rats, and food consumption normalized to metabolic weight of male (C) and female (D) rats age 8–22 wk. Rats were either sham-operated (Sham) or neutered (Neut) at 17–21 d. A subgroup of neutered females received 17ß-estradiol replacement (ERT) beginning at 8 wk. Values are means ± SEM, n = 8–9 (females) and 8–10 (males). Significantly different from sham-operated at the same age: aP < 0.05 (in some cases exceeding P < 0.0001). Significantly different from ERT at the same age: bP < 0.05 (in some cases exceeding P < 0.0001). Significantly different from the previous week: cP < 0.05 (in some cases exceeding P < 0.0001). Arrow indicates onset of 17ß-estradiol administration.

Study 2.

Study 2 examined the effects of hormones on the growth and food consumption of females with hormone replacement beginning 4 wk later than in Study 1. The effects of the estrogen receptor antagonist tamoxifen were also examined. As in Study 1, neutered females had significantly lower uterus weight and uterus/BW ratios than both sham-operated females and neutered females receiving ERT (Table 2 ). Neutered females receiving tamoxifen had uterus weights that were >75% lower than that of both sham-operated females and ERT females. Similar results were seen for uterus/BW ratios. Interestingly, when compared with neutered females, those receiving tamoxifen tended to have heavier uterus weights and uterus/BW ratios (P > 0.05).

View larger version (23K): [in this window] [in a new window]   Figure 5. Body weights of sham-operated (Sham) or neutered (Neut) female rats age 12–28 wk. Subgroups of neutered females received either 17ß-estradiol replacement (ERT) or tamoxifen (Tam) beginning at 12 wk. Values are means ± SEM, n = 4–7. Significantly different from sham-operated at the same age: aP < 0.01 (in some cases exceeding P < 0.0001). Significantly different from ERT at the same age: bP < 0.0001. Significantly different from neutered at the same age: cP < 0.0001. Significantly different from the previous week: dP < 0.05 (in some cases exceeding P < 0.001). Arrow indicates onset of 17ß-estradiol or tamoxifen administration.

View larger version (20K): [in this window] [in a new window]   Figure 6. Food consumption (A) and food consumption normalized to metabolic weight (B) of female rats age 12–28 wk. Rats were either sham-operated (Sham) or neutered (Neut) at 17–21 d. Subgroups of neutered females received either 17ß-estradiol (ERT) or tamoxifen (Tam) beginning at 12 wk. Values are means ± SEM, n = 4–7. Significantly different from sham-operated at the same age: aP < 0.05 (in some cases exceeding P < 0.0001). Significantly different from neutered at the same age: bP < 0.05 (in some cases exceeding P < 0.0001). Significantly different from ERT at the same age: cP < 0.05 (in some cases exceeding P < 0.01). Significantly different from the previous week: dP < 0.05 (in some cases exceeding P < 0.0001). Arrow indicates onset of 17ß-estradiol or tamoxifen administration.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Numerous studies have documented the effects of ovariectomy on absolute body weight in female rats; however, they have not systematically documented the weekly changes, the effects in the immediate postpuberty period and into adult ages or what effects estradiol and tamoxifen would have on these weekly changes. The current study fills in this missing information and documents the steady increase in this growth, and interestingly, demonstrates in females that food consumption does not account for these differences in body weight. The current studies demonstrated the pattern of weight gain and food consumption in male and female rats that underwent hormone manipulation before puberty, which occurs at 5–6 wk of age (10) . Not unexpectedly, males were somewhat larger than females even before puberty, by as much as 13%, despite similar food consumption normalized to metabolic weight. Neutering both male and female rats before puberty had significant but opposite affects on growth to maturity. In males, neutering reduced body weight, which was associated with reduced food consumption. In females, neutering significantly increased body weight, but this was associated with a reduction in food consumption. Replacement of estrogen to neutered females either immediately after puberty or later into adulthood reversed this effect, and produced an immediate and sustained reduction in body weight. Thus, in females, body growth is influenced by the ovarian hormone estradiol because initiation of ERT to neutered females prevented any further weight gain compared with both intact females and neutered females. When ERT in neutered females was delayed until well into the adult stage, a similar cessation of weight gain was seen. The SERM tamoxifen, administered to neutered females after the onset of normal puberty, also prevented any further weight gain.

Interestingly, data from the current study show that neutered males gained weight faster than neutered females, although by a smaller degree than occurred in intact animals. Thus, in both intact and neutered male rats, body weight increased at a greater rate than in females. This may be related to gender differences in the pattern of growth hormone secretion (13 14 15) . Evidence from the present study shows that the gonadal steroid hormones exert a modulating influence on this growth because the absence of testosterone lowered the maximal weight achieved but did not prevent steady increases, whereas the absence of estrogen significantly increased weight, an effect immediately attenuated by estradiol replacement. This effect was seen regardless of the age at which estradiol replacement was initiated.

Alterations in body composition have been documented to occur in neutered females, which may contribute to the alterations in weight. For example, female rats neutered at 28 d of age showed a higher water content but no change in whole-body fat at the age of 15 wk, although fat was redistributed to increased skin fat compared with control rats (1) . More recently, a cross-sectional study that examined healthy women aged 18–75 y showed that postmenopausal women had significantly higher fat content and lower lean tissue mass than premenopausal women (16) . These alterations in body composition presumably occurred in the present study, and may partially account for the different growth patterns observed in the female rats, ultimately contributing to the greater body weight in neutered females.

Results from the current study show that neutered females receiving estradiol replacement had significantly lower body weights than neutered females and sham-operated females. Interestingly, immediately after the initiation of ERT, food consumption normalized to metabolic weight was comparable to that of sham-operated females, whereas that of neutered females was significantly lower than that of the other groups. This suggests that the neutered females were either expending less energy than the others, or were more efficient at utilizing food energy. The hypophagic effects of estrogen are well established in a variety of species (3) . Recently, estrogen was found to augment the hypophagic effects of cholecystokinin in female rats, suggesting that its actions are targeted in the hypothalamic paraventricular nucleus (4) . Results from the current study suggest that although absolute food intakes were lower in females administered estrogen, when food intake was normalized to metabolic weight, food consumption was similar to that of sham-operated females. This suggests that although estrogen induces an overall reduction in food consumption, this is proportional to the reduction in body weight.

Study 2 was conducted to determine whether hormone replacement in neutered females would have a similar effect when initiated well into the adult age, and to assess the effect of treatment of neutered females with the SERM tamoxifen. Before the initiation of hormone replacement (12 wk of age), neutered females were significantly larger than intact females, and grew at a faster rate, as shown by the >30% steeper growth curve. This is comparable to the difference in slopes observed in Study 1 before the onset of treatment. With the onset of ERT, neutered females reached an immediate and sustained plateau in body weight as occurred in Study 1. Thus, the timing of the onset of estradiol replacement in female rats neutered before puberty does not influence the effects of estradiol on body growth. Also as occurred in Study 1, neutered females receiving estradiol had normalized food consumption similar to that of intact females. Interestingly, neutered females receiving tamoxifen also reached an immediate plateau in body weight after the initiation of treatment, at levels comparable to intact females. To our knowledge, this is the first study to demonstrate the estrogen-like effects of tamoxifen on weekly weight changes and food consumption. However, tamoxifen appears to be less potent than estradiol because neutered females receiving estradiol had significantly lower body weights than those receiving tamoxifen, who were comparable to sham-operated females. Neutered females receiving tamoxifen and neutered females receiving estradiol had generally similar food consumption, although tamoxifen-treated females consumed somewhat less than the group receiving estradiol, which was significant only at wk 16. This suggests that tamoxifen exerts a weaker effect on nutrition than estradiol because ERT and sham-operated females had similar normalized food consumption.

Tamoxifen is a potent nonsteroidal antiestrogenic agent utilized in the treatment of estrogen-responsive breast cancer, and has been suggested as a preventative agent in the development of this disease. However, it has also been shown to act as an estrogen agonist in other tissues, including the skeleton and cardiovascular system (17) . Previous studies have shown that daily subcutaneous administration of tamoxifen to female rats neutered postpuberty prevented weight gain with increasing age compared with intact controls, similar to the effects of daily estradiol (7) . This was associated with a significant reduction in body length and daily food intake. Results from the current study support this latter finding because food consumption was 10% lower than that of intact females. The tissue selective action of tamoxifen in the current study is illustrated by the uterus data. The uterus weight and uterus/BW ratio in neutered rats receiving tamoxifen generally were greater than those of neutered females, by as much as 36 and 54%, but were significantly lower than in females receiving estradiol. This suggests that tamoxifen had a modest estrogenic effect on the rat uterus. Similar results were reported by Kalu et al. (18) . This is in contrast with previous studies showing that in neutered female Wistar rats, daily oral tamoxifen did not increase uterine weight compared with untreated neutered females (19) . Differences between studies showing an estrogenic effect of tamoxifen in the uterus, including the present study, and those showing no such effect may be related to strain differences because identical doses (0.4 mg/kg) were used in the Kalu and Kafkasli studies. Results from the present study suggest that in neutered female WKY rats, in which plasma steroid levels are expected to be low, tamoxifen has an estrogenic effect on both body and uterus weight.

This study demonstrates that in male and female rats, weight gain and food consumption are modulated by sex hormones. Estrogen appears to have a greater effect than testosterone because neutering had a larger effect on body weight in females, and estrogen replacement immediately halted any further weight gain, irrespective of the age at which it was given. This cessation of weight gain was sustained throughout the period of treatment. The SERM tamoxifen also immediately reduced body weight, but was less potent than estrogen. Differences in food consumption do not appear to account for the effects of hormones and tamoxifen on body weight because there were no significant differences in food consumption between sham-operated animals and those receiving hormone replacement, despite significant differences in body weight. Thus, nutritional requirements are altered by hormone status.

	ACKNOWLEDGMENTS

 
The authors are grateful for the assistance of Warren Ball, Evelyn Bulczynski and Nesime Askin for looking after the rat colonies detailed in this study.

	FOOTNOTES

 
¹ Funded by a grant from the Heart and Stroke Foundation of Ontario (# T3775). W.J.W. was funded via Medical Research Council of Canada/K. M. Hunter Doctoral Research Award.

³ Abbreviations used: BW, body weight; ERT, estrogen replacement therapy; Neut, surgically neutered males/females; SERM, selective estrogen receptor modulator; Sham, sham-operated; Tam, neutered + tamoxifen; WKY, Wistar-Kyoto rats.

Manuscript received September 5, 2000. Initial review completed November 16, 2000. Revision accepted May 24, 2001.

	LITERATURE CITED

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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4. Flanagan-Cato L. M., King J. L., Blechman J. G. & O’Brien M. P. (1998) Estrogen reduces cholecystokinin-induced c-Fos expression in the rat brain. Neuroendocrinology 67:384-391.[Medline]

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6. Gray J. M. & Wade G. N. (1981) Food intake, body weight, and adiposity in female rats: actions and interactions of progestins and antiestrogens. Am. J. Physiol. 240:E474-E481.[Abstract/Free Full Text]

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