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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 61:419-426 (2006)
© 2006 The Gerontological Society of America

Positive Effects of 17ß-Estradiol on Insulin Sensitivity in Aged Ovariectomized Female Rats

Ana Alonso, Rebeca Fernández, María Moreno, Patricia Ordóñez, Héctor González-Pardo, Nélida M. Conejo, Fernando Díaz and Celestino González

Departments of 1 Functional Biology, Physiology Area and 2 Psychology, Laboratory of Psychobiology, University of Oviedo, Spain.

Address correspondence to Celestino González González, PhD, Assistant Professor of Physiology, Department of Functional Biology, Physiology Area, University of Oviedo, C/Julián Clavería s/n 33006, Oviedo, Spain. E-mail: tinog{at}uniovi.es


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Aging is associated with insulin resistance, which represents a common factor in age-related diseases. We aimed to determine the role of 17ß-estradiol on insulin sensitivity and memory during aging using ovariectomized rats (2–26 months of age) treated with physiological doses of 17ß-estradiol. Our results indicate a lack of effect of 17ß-estradiol replacement on spatial memory assessed in a water maze. Conversely, estradiol treatment improved insulin sensitivity in aging rats. These data imply that relatively low doses of 17ß-estradiol may have beneficial effects on glucose homeostasis due to the protective effects of estrogen. However, estradiol treatment used in the present study did not prevent memory impairment associated with aging.

AGING is strongly associated with a decline in insulin action, i.e., development of insulin resistance in humans and rodents (1,2). This condition contributes to progressive glucose intolerance (3) and the development of type 2 diabetes among elderly persons (4). In summary, aging is characterized by a decline in metabolic function, which may have particularly significant consequences not only on average life span, but also on quality of life in elderly persons.

The mechanisms underlying the increase in insulin resistance with advanced aged remain unclear; in the case of females, however, they appear to be related to loss of gonadal function, mainly due to a decrease in estrogen plasma level. Thus, previous studies (5–7) and various clinical observations (8,9) not only suggest an interaction between insulin and sex hormones, but also demonstrate that estrogen replacement therapy improves insulin sensitivity in postmenopausal women (10,11). However, the doses, route, and type of estrogens used appear to determine the efficacy of therapy. In this sense, the most important question is whether this type of therapy is a good tool against the inexorable consequences of aging on the metabolic function in women according to the risk/advantage ratio.

In addition, insulin resistance in elderly persons is associated with increased rates of atherosclerotic vascular disease, due in part to metabolic disorders such as hyperinsulinemia, dyslipidemia, and hypertension (termed metabolic syndrome). Therefore, insulin resistance represents an independent factor in the etiology of age-associated coronary and cerebrovascular disease (12,13). Moreover, several authors (14) suggest that depression, neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, and memory or cognitive dysfunction should be considered, in some cases, a result of metabolic syndrome and that postmenopausal women are more vulnerable to these diseases than are young women. These conditions suggest that the loss of gonadal function, associated with menopause, is determinant in the deleterious consequences of aging on the brain function. This view is supported by clinical data, which have shown that estrogen replacement therapy has a beneficial effect on improving memory processing and cognitive skills in postmenopausal women (15). Moreover, studies in female rats have demonstrated that protection against ischemic brain injury and its related mortality found in intact female rats disappears following ovariectomy (16) and can be restored by estrogen replacement (17). The beneficial effect of estrogen in the prevention and treatment of age-related physiological changes and in neurodegenerative diseases may be a result of neuroprotective effects and benefits of estrogen on the cognitive function, mostly due to estrogen having antioxidant properties (18,19).

In particular, estrogens can exert complex effects on learning and memory in rats. Rats show a clear cognitive decline with aging, similar to humans, and thus represent an appropriate animal model to study the effects of estrogens during aging. It has been previously reported that aged rats develop particular impairments in spatial learning and memory tasks (20–22). However, there is still much debate surrounding the effects of hormone replacement with estrogens on spatial learning and memory (23,24). In ovariectomized aged rodents, estrogen replacement improves (22,25), impairs (26), or has no effect (23,27) on spatial learning. Furthermore, this discrepancy involving potential benefits of estrogen replacement therapy on cognitive decline with aging has been reported in humans (28,29). Presumably, differences in the duration and beginning of hormonal treatments, dosage, and the behavioral tests used to evaluate the cognitive status may account for the apparent contradictory results.

Because it has previously been demonstrated that age-induced insulin resistance in rats is detectable at 4 months of age and that rats aged between 6 and 24 months of age represent a suitable animal model to study the "aging" phenomenon (30,31), we used ovariectomized rats treated with a physiological dose of 17ß-estradiol to determine the role of this hormone on decreased insulin sensitivity and ability for learning and memory processing that occur during aging.


   METHODS
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 Abstract
 Methods
Results
 Discussion
 References
 
Animals
Virgin female Wistar rats (from the Biotery of the Faculty of Medicine, University of Oviedo) weighing 250–280 g (age 8–10 weeks) and kept under standard conditions of temperature (23 ± 3°C), humidity (65 ± 1%), and a 12-hour light/dark cycle (8 AM to 8 PM) were used. The animals were fed a standard diet (Panlab A04; Barcelona, Spain) and had free access to water. All experimental manipulations were performed between 9:30 AM and 12:30 PM. All experimental procedures carried out with animals were approved by a local veterinary committee from the University of Oviedo vivarium, and subsequent handling strictly followed the European Communities Council Directive of November 24, 1986 (86/609/EEC).

Experimental Design
Rats were ovariectomized through a midline incision under light anesthesia by inhalation of halothane. Ovariectomized rats were separated randomly into two groups (control animals [V] and animals treated with 17ß-estradiol [E]) and were housed individually throughout the experiment.

All rats began the experimental treatment exactly 1 week after ovariectomy to ensure a uniform time of estrogen depletion before replacement and a recovery from surgery stress. At this time, the rats received subcutaneous implants in the posterior neck with 90-day-release 17ß-estradiol pellets or placebos (25 µg/day; Innovative Research of America, Sarasota, FL) containing no estradiol. Every 90 days the pellets were replaced. This dosing regimen has resulted in physiological levels of plasma estradiol (32) and has been shown to be neuroprotective in rats (33).

Groups (V and E) were divided randomly into 4 subgroups (7 animals/subgroup): 6, 12, 18, and 24 (according to the month of the experimental period in which the animals were killed). Therefore, the animals were killed when they were approximately 8, 14, 20, or 26 months old. Moreover, 14 more animals were killed 1 week after ovariectomy (age 9–11 weeks). Therefore, the animals included in this group did not receive any treatment. All of these animals were considered to be 0 month groups.

Spatial Learning Test
One week before death, animals were trained in a water maze to test spatial memory (34). The maze consisted of a circular pool made of black fiberglass, 1.5 m in diameter and 75 cm high. The pool was filled with tap water to a height of 32 cm, and a black escape platform was placed 2 cm beneath the water surface. The water temperature was kept at 23 ± 1°C during the entire test period. The experimental room had numerous visual cues such as colored maps, posters, and plastic dishes (all fixed on the walls) and a shelf, covered windows, and a table. Lighting was provided by two halogen spotlights (500 W) placed on the floor and facing the walls. Animal cages were kept outside the experimental room to avoid odor cues, and the bucket where the rats remained between consecutive trials was placed randomly around the pool during each trial. Maze performance was recorded live by using a video camera mounted in the ceiling and connected to a computerized video tracking system (EthoVision Pro; Noldus Information Technology, Wageningen, The Netherlands).

The pool was conceptually divided in four quadrants, according to the cardinal points (N, S, E, W). During the habituation day, rats were released facing the pool wall from the central border of each quadrant following a pseudorandom sequence, four times each session. Each rat received two daily sessions spaced 1 hour apart. Rats were returned to their home cages between sessions. The escape platform used on the first day was painted white and stood up 2 cm above the water surface. Rats were allowed to swim to locate the escape platform, where they remained for 15 seconds before they were placed in a black plastic bucket for 30 seconds. When rats failed to reach the platform within 60 seconds, they were gently guided to the platform. Because the platform is visible during the habituation day, the task can be considered as a test for visual acuity and sensorimotor coordination. Spatial learning took place during the following 4 days. Animals were trained daily using a single four-trial session. Testing was identical to that on the habituation day, but in this case the escape platform was hidden beneath the water surface. The platform was located in the same position across training days. Escape latencies and swimming paths were recorded using the video tracking system for each rat. Five minutes after finishing the last trial of the fourth training day, probe tests were performed. During the probe test, the escape platform was removed and rats were required to swim for 30 seconds. The percentage of total time spent in the quadrant was recorded for each animal.

Euglycemic Insulin Clamp
Clamp experiments were performed on anesthetized rats by the previously described procedure (5). When the experimental period was finished (0, 6, 12, 18, and 24 months), and after 12 hours of fasting, the animals were anesthetized with sodium pentobarbital (50 mg/kg), and the left saphenous vein was catheterized for insulin and glucose infusion.

Approximately 30 minutes after the end of surgery and as soon as anesthesia was assured by loss of pedal and corneal reflexes, to determine basal insulin concentration, a blood sample (2 ml) was collected from the jugular vein into heparinized tubes and centrifuged at 3000 rpm for 20 minutes at 4°C. Then plasma was immediately drawn off and stored frozen at –20°C until assayed. A blood sample for the determination of basal blood glucose was collected from the tail. Plasma glucose was measured using an Accutrend System (Accutrend Alpha; Roche Diagnostic S.L., Barcelona, Spain).

After the clamp study, blood samples (4 ml) for the determination of final insulin concentration, and 17ß-estradiol plasma concentrations were collected from the jugular vein into heparinized tubes and centrifuged at 3000 rpm for 20 minutes at 4°C. Then plasma was immediately drawn off and stored frozen at –20°C until assayed. The total blood volume taken was 5.5–6.5 ml from each animal. Plasma insulin was measured by radioimmunoassay using a DGR Instruments GmbH (Marburg, Germany) kit for rat insulin. The sensitivity of the assay was 0.1 ng/ml, and the intra-assay coefficient of variation was 9.32%. The sample was assayed in duplicate. Plasma 17ß-estradiol concentrations were analyzed using a commercially available radioimmunoassay kit with the coated tube technique (ICN Biomedicals, Inc., Barcelona, Spain). The assay sensitivity was 10 pg/ml, and the intra-assay coefficient of variation was 12.26%. All samples were measured on the same day. Finally, samples of different tissues were collected and immediately frozen in liquid nitrogen for future experiments, and animals were killed by bleeding.

Statistical Analysis
Data are expressed as mean ± standard error of the mean. Average daily escape latencies in the water maze within a group were analyzed using a one-way repeated-measures analysis of variance (ANOVA), followed by Student-Newman-Keuls post hoc tests to determine significant differences across training days. One-way ANOVAs were used to compare the performance of the experimental groups in the probe tests. Differences between vehicle- and estradiol-treated rats of each age group were assessed by comparing the mean escape latencies of the last training day using Student's t tests. Intra-group comparisons for the period of hormonal treatment were made using ANOVA or Kruskal–Wallis one-way ANOVA tests and the Student-Newman-Keuls test or Mann–Whitney U–Wilcoxon Rank Sum W test. A p ≤.05 was considered as significant. Statistical analysis was performed using SPSS for Windows (version 6.01, Apache Software Foundation; SPSS Inc., Chicago, IL).


   RESULTS
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 Abstract
 Methods
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Discussion
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Plasma 17ß-estradiol values observed throughout the study are shown in Figure 1. Obviously, estradiol plasma level was significantly higher in the E group than in the V group at any time of the experiment. In the E group, estradiol level increased significantly between 0 to 6 months and did not change significantly until the end of the experiment. However, we found a significant decrease in estradiol level in the V group between 0 and 6 months.


Figure 01
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  		Figure 1. Levels of 17ß-estradiol of vehicle (V = {blacksquare})-treated and estradiol (E = {square})-treated rats at 0, 6, 12, 18, and 24 months of age. Mean ± standard error of the mean for 7 animals. Significant differences are shown. * = V versus E; § = month versus next month

 
Figure 2 shows that body weight was significantly higher in the V group than in the E group, except at time 0 of the experiment. In contrast, in both groups we observed an increase in body weight throughout the study; however, only in the V group did we observe some significant increases: between 0 and 6, 12 and 18, and 18 and 24 months.


Figure 02
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  		Figure 2. Comparison of body weight of vehicle (V = {blacksquare})-treated and estradiol (E = {square})-treated rats. Mean ± standard error of the mean for 7 animals. Significant differences are shown. * = V versus E; § = month versus next month

 
Regarding spatial learning in the water maze, groups V and E at 0 months showed significant differences in the mean latency required to find the hidden platform among training days (p <.01; repeated-measures ANOVAs) (Figure 3). Post hoc analysis indicated that the performance of this group improved over time, as there was a significant decrease of escape latencies from day 2 onward (p <.05; Student-Newman-Keuls tests). However, no significant effects of training day on escape latencies were found in the remaining groups (6, 12, and 18 months). In addition, estradiol treatment did not have any effect on the escape latencies measured on the last training day in the latter groups (p >.05; Student's t tests). In the probe tests (Figure 4), there were statistically significant differences across groups (p <.01; one-way ANOVA). Further analysis demonstrated that only groups V and E at 0 months spent more time swimming in the correct quadrant as compared to the remaining groups (p <.05; Student-Newman-Keuls tests).


Figure 03
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  		Figure 3. Mean latencies (± standard error of the mean) to locate the platform across training days in the water maze for the experimental groups. Comparisons between vehicle (V = {blacksquare})-treated and estradiol (E = {square})-treated rats were not significant in any of the four treatment groups analyzed (A, 0 months; B, 6 months; C, 12 months; D, 18 months; n = 7 per group). Only V and E groups at 0 months showed a significant decrease in escape latencies with training days (p <.01)

 

Figure 04
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  		Figure 4. Probe trial performance as assessed by the percent time spent in the quadrant that previously contained the escape platform. *p <.05 versus groups treated at 6, 12, and 18 months of age with vehicle (V = {blacksquare}) or estradiol (E = {square})

 
Table 1 shows fasting blood glucose, fasting serum insulin, and serum insulin after clamp experiment. Fasting blood glucose levels were observed to be similar between groups and between months of the experimental period.


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  		Table 1. Fasting Blood Glucose, Fasting Serum Insulin, and Serum Insulin After Clamp Experiments Using Vehicle (V)-Treated and Estradiol (E)-Treated Rats at 0, 6, 12, 18, and 24 Months of Age.

 
Although in the E group, despite an increased tendency in fasting serum insulin levels, we did not find significant changes throughout the experimental period, in the V group we observed a significant increase between months 0 and 6 and 12 and 18 and a significant decrease between months 6 and 12 and 18 and 24. In contrast, fasting serum insulin was always significantly higher in the V group than in the E group.

Finally, in relation to serum insulin levels after clamp experiments, we found a significant increase throughout the experimental period in both the V and E groups. Moreover, this parameter was always significantly higher in the V group than in the E group.

To investigate insulin resistance in rats at different months of the hormonal treatment, we carried out glucose clamp experiments under euglycemic and hyperinsulinemic conditions. Figure 5 shows the results of the clamp experiments. After insulin infusion, blood glucose levels were similar between both groups at 0 and 6 months. However, at months 12 and 18 the levels were higher in the E group, and at month 24 they were higher in the V group (Figure 5, A–E). In contrast, the glucose infusion rates (Figure 5, F–J) of rats treated with 17ß-estradiol were significantly higher than those of the animals treated with placebo, indicating the superior insulin sensitivity in the E group.


Figure 05
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  		Figure 5. Blood glucose concentrations (A–E) and glucose infusion rate (F–J) during euglycemic clamp experiments. Data shown for experimental months 0 (A and F), 6 (B and G), 12 (C and H), 18 (D and I), and 24 (E and J). Values shown for vehicle (V = {blacksquare})-treated and estradiol (E = {square})-treated rats. Significant differences are shown. Comparisons between mean values from 40 to 60 minutes during euglycemic–hyperinsulinemic clamp experiments were evaluated. Mean ± standard error of the mean for 7 animals. * = V versus E

 
Figure 6 shows the comparison of glucose infusion rates as the mean values from 40 to 60 minutes during euglycemic hyperinsulinemic clamp experiments at months 0, 6, 12, 18, and 24. We used this parameter as an "in vivo" measure of insulin sensitivity. We observed a decrease in insulin sensitivity in the V group throughout the experimental period, but only increased statistical significance between months 0 and 6. However, in the E group we found a significant increase in insulin sensitivity between 0 and 6 months. Because insulin sensitivity decreased between month 6 and month 24, statistical significance increased between months 6 and 12 and 18 and 24. In contrast, it was interesting to prove that the insulin sensitivity was always significantly higher in animals treated with 17ß-estradiol.


Figure 06
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  		Figure 6. Comparison of glucose infusion rates of vehicle (V = {blacksquare})-treated and estradiol (E = {square})-treated rats. Glucose infusion rate was assessed as the mean values from 40 to 60 minutes during euglycemic–hyperinsulinemic clamp experiments. Mean ± standard error of the mean for 7 animals. Significant differences are shown. * = V versus E; § = month versus next month

 

   DISCUSSION
Top
 Abstract
 Methods
 Results
 Discussion
References
 
As previously reported, aging is associated with poor performance in the spatial learning task used (20,35), and appears not to correlate with a decline in visual acuity or sensorimotor ability. However, ovariectomy has little effect on spatial learning and memory evaluated in the water maze (24). In fact, it was previously demonstrated that the presence of endogenous or exogenous estradiol in female rodents actually impairs the escape latencies during training in the water maze (36,37) or has no effect (38,39). Moreover, estrogen replacement in ovariectomized rats showed no effects on spatial learning and memory in the radial-arm maze (27,40). Therefore, our results are in agreement with previous studies on the lack of effects of ovarian hormones on this particular spatial learning task.

Alternatively, estrogen replacement did not improve impairments in spatial learning when administered continually for 6, 12, 18, and 24 months. Unexpectedly, our findings do not confirm previous reports indicating that chronic estrogen replacement in ovariectomized rats may improve performance in water maze tasks (22,35). Perhaps, the physiological levels administered in our study were not sufficient to induce observable changes in spatial learning. On the contrary, other authors have indicated that the beneficial effects of estrogen replacement may be modulated during aging (25). Cholinergic deficits associated with aging may play an important role in cognitive impairment reported in aged rats, and long-term estrogen treatment may not be sufficient to restore these deficits as aging progresses (41). In addition, it should be considered that estradiol replacement used in the present study does not accurately reproduce the cyclic changes in estrogen levels produced by normal ovarian function. Thus, a high level of estrogens during the normal estrous cycle in the rat is inversely correlated with spatial learning ability (37,39).

The prevalence of impaired glucose tolerance and type 2 diabetes mellitus increases with age (42) not only in humans, but also in models of the aging rat (1,30). The mechanism underlying this phenomenon remains unclear. It may be possible that a decreased insulin sensitivity and/or impairment of ß-cell function are related (43,44). Alternately, it has been shown that the decrease of estrogens related to menopause is the main factor implicated in decreased insulin sensitivity and decreased insulin-mediated glucose uptake (45). This circumstance has an essential significance in the life of postmenopausal women because the insulin resistance and the related hyperinsulinemia are both part of the metabolic syndrome, which consists of diabetes, hypertension, hyperuricemia, lipid abnormalities, and alterations in thrombotic potential. This concept was initially described by Camus in 1966 (46), and popularized by Reaven in 1993 (47).

Several problems described above may be directly related to the increased intra-abdominal fat produced during aging (48). Our results correlate and are in agreement with body weight evolution (Figure 2), despite the fact that intra-abdominal fat was not specifically measured in our study. However, the anorexic effects of estradiol and the role of this steroid on leptin expression and secretion have previously been shown (5,7,49–51). Studies of leptin plasma levels and leptin expression, and a detailed study of the leptin receptor obtained from different tissue, are necessary and must be included in further studies, because different tissues (brain, adipose tissue, skeletal muscle) are implicated in the synthesis and regulation of leptin.

Several studies have previously shown that adult rats can be considered suitable animal models for studying the onset of the aging phenomenon (31,52), because at 6 months of age this animal displays signs of age-induced metabolic disturbances (30,53). Our present results are in agreement with this concept, because in the V group we found, during a 6-month experiment, a significant increase in fasting serum insulin and no changes in fasting blood glucose (Table 1), which are within normal range (53,54). It has previously been demonstrated that the increase in fasting serum insulin is due to impaired suppression of hepatic glucose production, which requires significant portal hyperinsulinemia (54). It is interesting that, in the present study, estradiol treatment prevented an increase in fasting serum insulin related to aging and lost ovarian function observed in the V group. Our results reveal that: (i) the reduced insulin action commonly described during aging is usually associated with a compensatory increase in plasma insulin, and (ii) estradiol is an essential factor in the modulation of glucose homeostasis during the aging process. Moreover, fasting blood glucose and fasting serum insulin in the V and E groups allow us to believe that a loss of sensitivity to insulin action in peripheral tissues rather than impaired insulin secretion primarily exists, and that the role of estradiol appears to improve peripheral insulin sensitivity, therefore preventing hyperinsulinemia. This finding may have particular importance because hyperinsulinemia is a common factor implicated in age-related diseases such as hypertension, stroke, type 2 diabetes mellitus, coronary heart disease, cancer, or neurodegenerative diseases.

However, the differences between fasting serum insulin and serum insulin levels following clamp experiments represent the insulin clearance rate (the liver being the most important tissue included in this process). We have found a significant increase in this parameter in both groups; therefore, the aging process impairs insulin clearance (Table 1). These results, in accordance with similar findings (55), suggest hepatic insulin resistance, which causes a decrease in the ability of insulin to modulate glycogen stores in aging (54). In this case, estradiol treatment also appeared to improve the insulin clearance rate, because serum insulin level following clamp experiments was significantly lower in the E group than in the V group (Table 1).

Finally, in view of the clamp experiments (Figures 5 and 6), it can, in general, be assumed that aging induces insulin resistance; however, this fact has been previously documented in human and animals (48,54). It is interesting to note that an estradiol dose, which has been shown to be neuroprotective in rats (33), is also capable of improving insulin sensitivity and delaying age- and loss of ovarian function–related insulin resistance. Therefore, our findings provide further evidence that insulin sensitivity represents a major independent factor in the etiology of age-associated coronary and cerebrovascular disease (12,13,30).

Conclusion
Our results confirm that aging and loss of ovarian function are associated with an impairment of glucose homeostasis; however, continuous administration of estradiol to maintain physiological plasma levels of this hormone markedly improves insulin sensitivity. These data imply that using a hypothetical hormonal therapy, with relatively low doses of 17ß-estradiol, may have beneficial effects on glucose homeostasis due to the protective effects of estrogen. However, the estradiol treatment used in our study was unable to prevent the memory impairment associated with aging. Because the present study is, to our knowledge, the first to use this hormonal treatment, further studies are necessary to demonstrate how estradiol is able to influence proteins implicated in intracellular insulin signaling in insulin-sensitive tissue such as liver, skeletal muscle, and adipose tissue and other organs especially affected by aging, such as brain.


   Acknowledgments
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 Abstract
 Methods
 Results
 Discussion
 References
 
This study was supported by Fondo de Investigaciones Sanitarias (FIS Ref: PI020324) and Ministerio de Educación y Ciencia (MEC Ref: SEJ2004-07445/PSIC).


   Footnotes
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Decision Editor: James R. Smith, PhD

Received July 26, 2005

Accepted October 18, 2005


   References
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 Results
 Discussion
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A. Alonso, M. Moreno, P. Ordonez, R. Fernandez, C. Perez, F. Diaz, A. Navarro, J. Tolivia, and C. Gonzalez
Chronic Estradiol Treatment Improves Brain Homeostasis during Aging in Female Rats
Endocrinology, January 1, 2008; 149(1): 57 - 72.
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