Effects of Dehydroepiandrosterone on Gross Morphology and Behavior of Perimenopausal Rats

Egyptian Academic Journal of Biological Sciences is the official English language journal of the Egyptian Society of Biological Sciences, Department of Entomology, Faculty of Sciences Ain Shams University. The Journal publishes original research papers and reviews from any zoological discipline or from directly allied fields in ecology, behavioral biology, physiology & biochemistry. www.eajbs.eg.net Provided for non-commercial research and education use.  Not for reproduction, distribution or commercial use.

products Regulatory Agency (MHRA).The capsules were opened and the powder was suspended in sesame oil purchased from El Captin Pharmaceutical Company (Cairo, Egypt).All other chemicals were obtained from El-Nasr pharmaceutical chemicals co.(Cairo, Egypt).

Experimental animals:
Healthy young adult female albino rats (4 to 5-months-old) weighing 120-160 g, and perimenopausal rats (10 to12-months-old) weighing 200-250 g, were obtained from the Medical Research Center at the Faculty of Medicine, Ain Shams University (Cairo, Egypt).The animals were given free access to water and standard rat chow, and were allowed 2 weeks to acclimatize before the start of any experimental procedure.

Experimental protocol:
Rats were divided into five groups, each of 5 rats, as follows: -Group I: Control young adult rats (4 to 5-month-old).
-Group III: Perimenopause rats orally treated with DHEA at a dose of 50 mg/kg b.wt.
-Group IV perimenopause rats orally treated with DHEA at a dose of 75 mg/kg b.wt.
-Group V perimenopause rats orally treated with DHEA at a dose of 150 mg/kg b.wt.
DHEA was given daily for 2 months.Control animals were given the vehicle in a similar manner.

Statistical analysis:
Numerical data are reported as mean values and standard deviation.GraphPad Prism (version 5.0, GraphPad software, San Diego, CA, USA) was used to conduct all statistical analysis.Data were analyzed statistically using One-way ANOVA followed by post hoc multiple comparisons (Tukey's test) for comparative analysis between the groups.P<0•05 was regarded as statistically significant.

Fur examination:
At the end of the experiment, the fur of perimenopausal rats was lighter than those of the young adult rats.Treating perimenopausal rats with DHEA resulted in fur loss in a dose-related manner.In rats treated with the low dose of DHEA, the fur density was almost similar to the corresponding perimenopausal control rats.On the other hand, perimenopausal rats treated with the moderate or high dose of DHEA showed moderately hair loss compared to the perimenopausal control rats (Fig. 1).

Body weight change:
At the end the experiment, there was increase in the body weight in young and perimenopausal control groups.The increase in the final body weight of perimenopausal rats was significantly more than noted in that of young adult rats.The difference between final and initial body weights was decreased in all perimenopausal-treated rats in comparison with that of perimenopausal control rats.Moreover, body weight gain of DHEA-treated rats was decreased in a positive relation to the dose concentrations as shown in Table 1.

Table 1: Effect of DHEA on the body weight of perimenopausal rats
Values are expressed as means ± SEM. * indicates the significant difference of perimenopausal control group vs. the corresponding young control group, **P<0.01.

Behavioral changes
There was no treatment-related death in any of treated rats along the experiment duration.In the beginning of the experiment, there was decrease in the food intake in perimenopausal-treated rats compared to their corresponding control ones, which was slightly improved by time.The activity and locomotion were obvious in young adult rats, but these behaviors in perimenopausal rats were relatively less than observed in the young rats (Table 2).
Young and perimenopausal rats can walk and interact freely in the cage.While, perimenopausal treated rats with different doses of DHEA had latency and frequency of the agonistic behaviors biting, sideway threats, upright postures, and aggressive grooming till the end of the first month of the experiment, then by time these behavioral changes were decreased leading to depression-like behavior, which was represented by decrease in food intake or body gain, locomotion, and activity.The decrease in locomotion, activity, and depression was more obvious in the end of the experiment and especially in high dose-treated rats compared to other doses-treated and control rats (Table 2).

Mean of weight change Table 2: Effect of DHEA on behavioral parameters of perimenopausal rats
Values are expressed as means ± SEM. † indicates significant difference of DHEA-treated groups vs. the perimenopausal control group, †p<0.05,† †p<0.01,† † †p<0.001.

DISCUSSION
The present experiment was designed to assess the potential side effects of therapeutic doses of DHEA in perimenopausal rats.The present results showed that all rats gained weight during the course of the experiment.The body weight gain of perimenopausal rats was significantly more than that noted in young adult rats.However, Yin et al. (2015) reported that the change in body weight between the young and old rats is insignificant.On the other hand, DHEA-treated perimenopausal rats gained less body weight than observed in non-treated perimenopausal rats.The decrease in body weight gain was dose-dependent.This observation in in line with previous studies, which reported that DHEA administration reduce body weight gain (Shepherd and Cleary, 1984;Cleary and Zisk, 1986;Cleary, 1991;Svec et al., 1995;Abadie et al., 2000;Zhao et al., 2007;Ma et al., 2008;Hakkak et al., 2010Hakkak et al., & 2017)).The decrease in body weight gain may be related to the decrease in food intake (Weindruch et al., 1984), or related to the decrease the abdominal or body fats (Cleary and Zisk, 1986;Villareal and Holloszy, 2004;Ma et al., 2008).However, other studies reported that DHEA treatment causes a decrease in the body weight (Tagliaferro et al., 1986;Mohan et al., 1990;Yamada et al., 1991;Han et al., 1998;Ng et al., 1999;Richards et al., 2000;Kopplow et al., 2005;de Heredia et al., 2007;Caldwell et al., 2014;Chen et al., 2015), and other studies found no effect for DHEA on body weight (Lea-Currie et al., 1997 a, b;Aragno et al., 2004;Sander et al., 2006;Miyazaki et al., 2016).The cause for the observed difference in body weight could be attributted to different DHEA regimes (de Heredia, et al., 2007), or due to different routes of DHEA administration that might lead to differences in circulating DHEA levels and differences in body weight (Miyazaki et al., 2016).
There are many studies reported various side effects for DHEA, including acne, hair loss, hirsutism and deepening of voice, have been reported with the use of physiological doses of DHEA in women (Legrain et al., 2000;van Vollenhoven, 2002;Sadock & Sadock, 2008;Gleicher and Barad, 2011;Traish et al., 2011;Yakin and Urman, 2011).Facial hair growth and voice changes may be irreversible (Sadock & Sadock, 2008).
In the present study, DHEA administration exhibited hair loss as a side effect.This side effect was in a positive relation to the studied doses.This observation is in agreement with other clinical studies (Barad et al., 2007;(Sadock and Sadock, 2008;Gleiccher et al., 2009Gleiccher et al., & 2010;;Gleicher and Barad, 2011;Yakin and Urman, 2011).The hair loss effect of DHEA is primarily related to androgen effects as reported by Gleiccher et al. (2009) and Gleicher and Barad (2011).
The present experiment also assessed the effect of DHEA administration on behavioral changes in perimenopausal rats.DHEA-treated animals showed depression-like behavior, manifested by decreased activity and food intake.DHEA is known to influence a variety of behaviors, including cognition and mood (Maninger et al., 2009).The decrease in food intake is in line with the result of Weindruch et al. (1984); while Sato et al. (2012) reported that DHEA administration do not decrease the food intake.The study of Minkin et al. (1993) reported that anabolic steroids decrease locomotor activity in rats.On the other hands, other studies reported that anabolic steroids may increase aggressive behavior in laboratory animals (Scholtens et al., 1988) and in humans (Hannan et al., 1991).These contradictory findings could be attributted to different experimental designs, animal species, drug dose, duration, and mode of administration.
Since DHEA is a biosynthetic precursor of all steroid hormones, including E2 (Traish et al., 2011), so its administration would definitely lead to the increase in serum E2 level.Therefore, the current results explanation may be related to the effect of E2.This is in consistent with Tsutsui and lshii (1981), who showed that injection of a sufficient amount of E2 is effective in inducing aggressive behavior in birds.While Wada (1982) reported that E2 did not fully enhance locomotor activity, nor did it fully improve sexual behavior.On the other hand, Taylor et al. (2012) hypothesized that DHEA has a direct influence on behaviors and this effect is not simply destined to an indirect manner by conversion to E2 or testosterone.
Based on the current data, high doses of DHEA have adverse effects on body weight, fur density, and behavior of perimenopausal rats.