Abstract: Studies have shown that hormonal changes that occur during menstrual or oestrous cycle influence angiotensin-induced water intake. However, little is known about the effects of Oral Contraceptive (OC) on body weight and eating habit when Renin-Angiotensin System (RAS) is suppressed. This study documents the effect of OC on weight gain and food and water consumption. It also assesses whether suppression of RAS by captopril would affect OC-induced changes. Forty female rats, distributed into 4 groups (10 rats in each), were used for the experiment. Vehicles-treated, OC-treated, captopril-treated and OC+captopril-treated groups. The OC used contained 1.0 μg ethinyloestradiol and 10.0 μg norgestrel. Body weight, food and water intake were recorded daily throughout the experiment period. Food and water consumed per day per 100 g body weight was also calculated. The OC-treated and OC+captopril-treated rats had significantly lower body weight when compared with those of vehicle treated and captopril-treated rats. The OC-treated rats consumed significantly less food than vehicle-treated and captopril-treated groups. OC+captopril-treated rats consumed significantly less food than other groups. The OC administration is associated with reduction in weight gain and food and water consumption. Co-administration of captopril significantly augments this effect.
INTRODUCTION
A number of behavior has been demonstrated to be influenced by fluctuations in ovarian hormonal levels during menstrual cycle in women. Among the behavior are sexual receptivity, dressing, choice of colour, appetite, food ingestion and water consumption (Hee and Tokura, 1995; Wallen et al., 2001). Studies have also shown that ovarian hormones can modulate body weight, appetite, food and water ingestion (Kisley et al., 1999; Wallen et al., 2001; Akhigbe et al., 2008).
It has been reported in female rats that spontaneous drinking and thirst elicited via the activation of Renin-Angiotensin System (RAS) is attenuated at oestrous (Findlay et al., 1979; Krause et al., 2003). It has also been shown that administration of oestrogen to ovariectomized female rats results in reduction of food and water consumption (Wallen et al., 2001; Krause et al., 2003). Oestrogen administration has been demonstrated to cause attenuation of water intake in response to peripheral intracerebroventricular administration of angiotensin II (ang II) (Findlay et al., 1979).
On the other hand, administration of progesterone-only has been reported to increase body weight, food and water intake in ovariectomized female rats (Gray and Wade, 1981; Kisley et al., 1999). Studies have shown that suppression of cyclic fluctuation of ovarian hormones with long-term use of Oral Contraceptive (OC) is not associated with increase in body weight (Brill et al., 1994; Oelkers et al., 1995; Rosenberg, 1998). Despite these reports, it is a common perception the OC causes weight gain.
Therefore, the purpose of this study is to determine whether the use of combined OC causes fluctuation in body weight, food and water intake and to investigate the possible role of RAS.
MATERIALS AND METHODS
Experiments were conducted in 40 rats aged 10-12 weeks. They were distributed into 4 groups (10 rats in each), housed in a wire-bottomed, stainless steel cages in a well-ventilated, temperature controlled room (25°C) on 12:12 h light-dark cycle.
Vehicles-treated received 2 mL olive oil/100 g body weight daily intragastrically, OC-treated group received OC containing 1.0 μg ethinyloestradiol and 10.0 μg norgestrel (Wyeth Ayerst, Inc., Canada) intragastrically, captopril-treated group received captopril (SQ-14225, Bristol-Meyers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA) dissolved in tap water to achieve a dose of 0.1 mg mL-1, OC+captopril-treated group received OC as in OC-treated group as well as captopril as in captopril-treated group. Rats were fed ad lib’itum. All experimental procedure conformed to the guideline of Guiding Principle for Research Involving Animals.
Body weight, food and water intake were recorded daily throughout the 9 weeks of the experiment between 08:00 and 11:00 h. Food and water consumed per day per 100 g body weight was also calculated.
Data were analysed using SPSS version 11.0: Analysis of Variance (ANOVA) was performed in all the data and the Bon Ferroni’s test was used as a post-hoc test with the significant level set at p<0.05. Data are presented as mean ± standard error of mean (SEM).
RESULTS
The OC-treated and OC+captopril-treated rats weighed significantly less than vehicle -treated captopril-treated rats between 8th and 9th week of treatment (Fig. 1).
The OC-treated and OC+captopril-treated rats consumed significantly less food than the other groups throughout the experimental period (Fig. 2), except on the 6th week of treatment (Fig. 2). Food consumed by OC+captopril-treated rats were significantly less than that of the OC-treated rats in the 9th week of treatment (Fig. 2).
Water intake decreased significantly from the 4th to 9th week of treatment in OC-treated and OC+captopril-treated rats, while the captopril-treated group consumed significantly more water in the 5th and 7th week (Fig. 3). Water intake increased significantly in captopril-treated rats when compared with other groups, while OC+captopril group consumed lowest volume of water.
| Fig. 1: | Effect of oral contraceptive and captopril on body weight.
*p<0.05 vs. vehicle-treated, #p<0.05 vs. captopril-treated |
| Fig. 2: | Effect of oral contraceptive and captopril on food ingestion.
*p<0.05 vs. vehicle-treated, #p<0.05 vs. captopril-treated |
| Fig. 3: | Effect of oral contraceptive and captopril on water intake.
*p<0.05 vs. vehicle-treated, #p<0.05 vs. captopril-treated |
DISCUSSION
Studies have documented variable effect of hormonal contraceptive on absolute body weight in women (Brill et al., 1994; Oelkers et al., 1995; Berenson and Wiemann, 1995; Rosenberg, 1998; Pelkman et al., 2001) and in female Sprague-Dawley rats (Fowler et al., 1985). However, they have not systematically documented the weekly changes or what effect ang I-converting enzyme inhibitor (ACE-inhibitor), captoril, would have on these weekly changes. This study seems to be the first to provide information and document the steady changes in body weight with its relation to food and water intake. This study also demonstrates the effects of captopril on OC-induced changes.
In present findings, administration of combined OC steroid were consistent with studies in female rats fed on combined OC steroid (Fowler et al., 1985; Ciavatti et al., 1989; Akhigbe et al., 2008) and with a large study in 4746 adolescent users of a low dose combine OC (Brill et al., 1994). Evidence from this study shows that the OC steroids used in this study exert a modulating influence on the body weight, because the vehicle-treated rats, where endogenous ovarian hormones may be suppressed, had significant weight gain than OC-treated rats. Previous studies have demonstrated that administration of oestradiol reduced body weight gain, while administration of progesterone increased weight gain (Schwartz and Wade, 1981; Gray and Wade, 1981). The fact that administration of a combined OC steroid reduced body weight gain suggests that the oestrogen component of the OC steroid may be responsible for the loss of body weight.
Observations in this study show that OC-treated rats had a decrease in food and water consumption. This is consistent with previous studies (Schwartz and Wade, 1981; Wallen et al., 2001; Akhigbe et al., 2008) but inconsistent with respect to administration of oestrogen-only and in combination with progesterone (Fregly et al., 1985). The decrease in weight caused by OC administration is likely due to the observed reduction in food and water consumption. Interestingly, OC-treatment produced reduction in food and water intake in the 4th week of treatment earlier than the reduction in body weight, which started in the 7th week of treatment. This study provides evidence that reduction in body weight seen in OC-treated rats is likely to be a secondary effect to the hypophagic and hypodipsogenic effect of OC steroids.
The OC use as be shown to stimulate RAS activity and thus found to increase plasma concentration of ang II, the effector substance of the RAS (Gray and Wade, 1981; McNeil et al., 1988). Angiotensin II has been documented to act on CNS and regulate the feeding and drinking habit in rats (Fowler et al., 1985; Kisley et al., 1999; Pal et al., 2000). However, the results of this finding suggest that the direct effect of OC to suppress water intake overrides the effect of RAS to induce drinking.
We found that drinking habit in captopril-treated rats was improved when compared to the control rats. This is in consonance with previous studies (Rowland et al., 1996, 1997; Thunhorst and Johnson, 2003). The decrease in food and water intake found in OC-treated rats and OC+captopril-treated rats relative to the vehicle-treated and captopril-treated rats may also suggest the anti-dipsogenic effect of OC steroids as previously demonstrated by the administration of oestrogen-only or in combination with progesterone (Kisley et al., 1999; Akhigbe et al., 2008).
The co-administration of captopril significantly augmented anti-dipsogenic effect of OC as observed in OC+captopril-treated rats. This suggests that ang II-induced thirst is blunted by OC therapy and augmented in combination with captopril.
The administration of combined OC steroid has similar effect on food and water intake and appears to provide a means to associate these ingestive behavior. Our results are in agreement with previous results, which show that oestrogen therapy reduces body weight (Donohoe and Steven, 1982, 1983; Thunhorst and Johnson, 2003). This result strongly supports that the antidipsogenic effect of OC steroids seen in these rats is not merely secondary to its hypophagic and anorectic effect, but it is an independently modulated mechanism, possibly via the shigher centers.
CONCLUSIONS
Long-term use of synthetic oral oestrogen, ethinyloestradiol, in combination with progestogen, norgestrel, at a dose high enough to suppress cyclic fluctuation of endogenous ovarian hormones, significantly reduces body weight gain, possibly by decreasing food and water consumption. The effect is augmented by ang-I converting enzyme inhibitor, captopril. The results of this study also suggest an interaction between OC steroid, captopril and the activation of RAS.