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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 13  |  Issue : 2  |  Page : 98-102

Vitamin C alleviates surgical castration-induced dyslipidemia in male rats


1 Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
2 Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin; Department of Standards and Quality Assurance, National Health Insurance Scheme, North Central A Zonal Office, Kwara State Ministry of Health Premises, Fate, Kwara, Nigeria
3 Department of Anatomy, College of Health Sciences, University of Ilorin, Ilorin, Nigeria

Date of Web Publication4-Aug-2016

Correspondence Address:
Abdullateef I Alagbonsi
Department of Standards and Quality Assurance, National Health Insurance Scheme, North Central A Zonal Office, Kwara State Ministry of Health Premises, Fate, Ilorin, Kwara
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0189-7969.187706

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  Abstract 

Background and Aims: Androgen deprivation has been shown to be associated with dyslipidemia. Ameliorative effect of Vitamin C on dyslipidemia has also been reported. This study aimed at investigating the role of Vitamin C supplementation in castration-induced dyslipidemia.
Materials and Methods: Twenty male rats were randomly divided in a blinded fashion into 4 groups (n = 5 each): Groups I and II were sham-castrated and received normal saline (1 ml/kg) and 1.25 g/kg Vitamin C, respectively, whereas Groups III and IV were rendered bilaterally castrated and received normal saline (1 ml/kg) and 1.25 g/kg Vitamin C for 4 weeks.
Results and Conclusions: Castrated rats had reduced high-density lipoprotein, testosterone, estradiol, but increased low density lipoprotein, triglycerides, total cholesterol, and Castelli index and had no effect on follicle stimulating hormone when compared to sham-operated rats. Vitamin C supplements improved these parameters in normal and castrated rats. This study showed that castration-associated dyslipidemia and atherogenic risk in male rats is dependent on testosterone and estradiol. In addition, Vitamin C improves these parameters in normal and castrated rats by increasing testosterone and estradiol production, possibly from extra-testicular sites. However, there is a need for further study to ascertain the actual extra-testicular testosterone and estradiol production site.

Keywords: Atherogenesis, castration, lipid profile, reproductive hormones, Vitamin C


How to cite this article:
Olayaki LA, Alagbonsi AI, Adamson M, Ayodele OD, Oyewopo AO. Vitamin C alleviates surgical castration-induced dyslipidemia in male rats. Nig J Cardiol 2016;13:98-102

How to cite this URL:
Olayaki LA, Alagbonsi AI, Adamson M, Ayodele OD, Oyewopo AO. Vitamin C alleviates surgical castration-induced dyslipidemia in male rats. Nig J Cardiol [serial online] 2016 [cited 2020 Oct 23];13:98-102. Available from: https://www.nigjcardiol.org/text.asp?2016/13/2/98/187706


  Introduction Top


Castration, an effective treatment for prostate tumors, is associated with considerable side effects that include cardiovascular disorders [1],[2] and metabolic syndrome. [3] Although several medical regimens have been developed, [4] their impact on minimizing its side effects and improving the quality of life is still under discussion. Herbal and dietary supplements appeal to patients because they are perceived as being "natural" with fewer side effects than prescription medicines. [5],[6]

Vitamin C is a water-soluble vitamin that is found intra- and extra-cellularly as ascorbate. [7] It is a natural antioxidant that prevents free radicals production caused by oxidative damage to lipids and lipoproteins in various cellular compartments and tissues. [8] The beneficial effect of Vitamin C on lipid profile and lipid metabolism has been well documented. For instance, there are previous studies that reported Vitamin C to decrease serum cholesterol in normal humans and animals. [9] Similarly, Vitamin C was shown to attenuate the increased lipid profile associated with hyperglycemia, [10] diabetes, [11] renal failure, [12] artherosclerosis, [13] and hypertension. [9] Moreover, Vitamin C has been shown to protect the prostate from testosterone-induced tumors. [14]

This study aimed at investigating the possible ameliorative effect of Vitamin C on surgical castration-induced dyslipidemia in male rats.


  Materials and methods Top


Twenty male albino rats weighing between 200 and 250 g were obtained from the Animal House of the Department of Biochemistry, Faculty of Life Sciences, University of Ilorin, Kwara State, Nigeria. They were housed at room temperature with free access to food and water ad libitum and were maintained on a 12-h light/dark cycle, with the lights on from 7:00 am. "Principles of laboratory animal care (NIH publication No. 85-23, revised 1985)" were followed. All experiments have been examined and approved by the Institutional Ethics Committee.

Experimental protocol

After 2 weeks acclimatization to their new environment with standard laboratory diet and water given ad libitum, the 20 animals were randomly divided in a blinded fashion into four groups (n = 5 each): Groups I and II were sham-operated and received normal saline (1 ml/kg) and 1.25 g/kg Vitamin C, [15] respectively, for 4 weeks. Groups III and IV were rendered bilaterally castrated and received normal saline (1 ml/kg), or 1.25 g/kg Vitamin C for 4 weeks.

Bilateral orchidectomy (surgical castration) was induced as previously described. [16] Briefly, under strict aseptic conditions, the animals were anesthetized with ketamine (75 mg/kg). An incision was made on the scrotum, followed by gentle mobilization of the testis through the incision. The sham-operation followed the same procedure, but the testis was left in the scrotum. All the animals subsequently recovered fully. Animals were sacrificed a day after the last treatment under ketamine anesthesia, and a blood sample from each rat was collected (by cardiac puncture) into lithium heparinized capillary tubes. Plasma was collected from each sample and preserved at −20°C.

Estimation of lipid profile and hormones

The levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides (TGs), and total cholesterol (TC) were determined spectrophotometrically with microplate reader (Spectramax plus, Molecular devices, Sunnyvale, CA, USA) following the kit manufacturer's procedures and as previously described. [10] Atherogenic risk or Castelli index were defined as the result of dividing the TC by the HDL, both expressed in mg/dl. [17]

Plasma testosterone, estradiol, and follicle stimulating hormone (FSH) were also assayed spectrophotometrically (Spectramax plus, Molecular devices, Sunnyvale, CA, USA) following the kits' manufacturer procedures.

Data processing

Data were analyzed with one-way ANOVA using GraphPad Prism version 5.0.3.0 (San Diego CA, USA), followed by a post hoc least significance difference test for multiple comparisons. Data were presented as the mean ± standard error of mean. The values of P ≤ 0.05 were considered statistically significant.


  Results Top


Effects of Vitamin C on lipid profile and atherogenic risk in sham-operated and castrated rats

The plasma HDL concentration was significantly lower (P < 0.001) in castrated rats that received normal saline (35.8 ± 3.8) than in sham-operated rats that received normal saline (62.37 ± 3.26). The HDL in sham-operated rats that received Vitamin C (84.67 ± 3.02) was significantly higher (P < 0.001) than in sham-operated rats that received normal saline (62.37 ± 3.26). Similarly, the HDL in castrated rats that received Vitamin C (74.00 ± 2.14) was significantly higher (P < 0.001) than in castrated rats that received normal saline (35.8 ± 3.8) [Table 1].

The plasma LDL concentration was significantly higher (P < 0.001) in castrated rats that received normal saline (57.90 ± 0.70) than in sham-operated rats that received normal saline (35.23 ± 0.93). The LDL in sham-operated rats that received Vitamin C (23.37 ± 0.47) was significantly lower (P < 0.001) than in sham-operated rats that received normal saline (35.23 ± 0.93). Similarly, the LDL in castrated rats that received Vitamin C (33.77 ± 2.84) was significantly lower (P < 0.001) than in castrated rats that received normal saline (57.90 ± 0.70) [Table 1].
Table 1: Effects of Vitamin C on lipid profile and atherogenic risk in sham-castrated and castrated rats


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The plasma TGs concentration was significantly higher (P < 0.001) in castrated rats that received normal saline (158.20 ± 5.90) than in sham-operated rats that received normal saline (130.93 ± 2.96). The TG in sham-operated rats that received Vitamin C (123.63 ± 1.81) was lower, albeit insignificant (P > 0.05), than in sham-operated rats that received normal saline (130.93 ± 2.96). Similarly, the TG in castrated rats that received Vitamin C (114.23 ± 1.60) was significantly lower (P < 0.001) than in castrated rats that received normal saline (158.20 ± 5.9) [Table 1].

The plasma TC concentration was significantly higher (P < 0.001) in castrated rats that received normal saline (100.00 ± 1.70) than in sham-operated rats that received normal saline (73.67 ± 2.77). The TC in sham-operated rats that received Vitamin C (90.30 ± 4.90) was significantly higher (P < 0.001) than in sham-operated rats that received normal saline (73.67 ± 2.77). However, the TC in castrated rats that received Vitamin C (86.37 ± 3.18) was significantly lower (P < 0.05) than in castrated rats that received normal saline (100.00 ± 1.70) [Table 1].

The Castelli index (atherogenic risk) was significantly higher (P < 0.001) in castrated rats that received normal saline (2.83 ± 0.35) than in sham-operated rats that received normal saline (1.19 ± 0.07). There was no significant difference (P > 0.05) in the atherogenic risk of sham-operated rats that received Vitamin C (1.07 ± 0.08) and sham-operated rats that received normal saline (1.19 ± 0.07). However, the atherogenic risk in castrated rats that received Vitamin C (1.17 ± 0.07) was significantly lower (P < 0.001) than in castrated rats that received normal saline (2.83 ± 0.35) [Table 1].

Effect of Vitamin C on plasma reproductive hormones in sham-operated and castrated rats

The plasma testosterone concentration in castrated rats that received normal saline (0.30 ± 0.00) was significantly lower (P < 0.01) than in sham-operated rats that received normal saline (1.47 ± 0.09). The testosterone in sham-operated rats that received Vitamin C (3.67 ± 0.38) was significantly higher (P < 0.001) than in sham-operated rats that received normal saline (1.47 ± 0.09). Similarly, the castrated rats that received Vitamin C (0.75 ± 0.01) had slightly higher, albeit insignificant (P > 0.05), testosterone concentration than the castrated rats that received normal saline (0.30 ± 0.00) [Table 2].
Table 2: Effects of Vitamin C on plasma testosterone, estradiol, and follicle stimulating hormone concentrations in sham-castrated and castrated rats


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The plasma estradiol concentration in castrated rats that received normal saline (1.30 ± 0.00) was significantly lower (P < 0.05) than in sham-operated rats that received normal saline (2.70 ± 0.20). The estradiol in sham-operated rats that received Vitamin C (4.80 ± 0.15) was significantly higher (P < 0.01) than in sham-operated rats that received normal saline (2.70 ± 0.20). Similarly, the estradiol in castrated rats that received Vitamin C (4.60 ± 0.60) was significantly higher (P < 0.001) than in castrated rats that received normal saline (1.30 ± 0.00) [Table 2].

There were no significant differences (P > 0.05) in the plasma FSH concentration in sham-operated rats that received normal saline (3.32 ± 0.17) or Vitamin C (3.15 ± 0.07) and castrated rats that received normal saline (3.86 ± 0.04); whereas castrated rats that received Vitamin C (5.00 ± 0.50) had significantly higher FSH than all of them (P < 0.01, P < 0.001, and P < 0.05, respectively) [Table 2].


  Discussion Top


Epidemiological data suggest that testosterone levels are negatively associated with TC, LDL, and TG, [18] whereas its levels appear to have a complicated and controversial relationship with HDL levels and cardiovascular risk in men. For instance, androgen levels within the normal adult male range were found to have a suppressive effect on HDL. [19] On the other hand, several studies on patients with coronary artery disease have shown that higher testosterone levels are associated with higher HDL concentrations. [20] The increase in LDL, TG, TC, and atherogenic risk but decrease in HDL in castrated rats in this study is in agreement with previous epidemiological studies which showed that low testosterone is related to elevated TC, [21],[22] TG, [23] LDL [22] and decreased HDL [21],[22],[23] and an increased incidence of dyslipidemia [24] in men. Since these parameters constitute risk factors for various cardiovascular diseases, their high levels in castrated rats might be responsible for high mortality from cardiovascular diseases observed in prostate cancer (PCa) patients undergoing different forms of androgen deprivation therapy (ADT), for example, castration.

The previous study has shown that Vitamin C is a potent antioxidant that inhibits the oxidation of HDL [25] and LDL. [26] In addition, Anderson et al.,[27] and Bsoul and Terezhalmy [28] noted that animal fed on Vitamin C had reduced the risk of coronary heart disease. Similarly, Vitamin C administration to castrated rats in this study reduced LDL, TG, TC, and atherogenic risk but increased HDL not only in normal rats, but also in castrated rats. This may be linked to the ability of Vitamin C to enhance the activation of 7α-hydroxylase (the enzyme that converts plasma cholesterol to bile acid), in addition to the fact that its deficiency causes inhibition of this enzyme in guinea pigs. [29]

Steroid hormones synthesis requires cholesterol as the precursors. In this study, castration is associated with increased cholesterol but reduced testosterone and estradiol. Although a reduced plasma testosterone and estradiol were expected following the removal of testis which is the major site of secretion of these steroid hormones, however, increased cholesterol induced by castration was anticipated to elicit increased extra-testicular production of these hormones. Since Vitamin C plays a direct role in hydroxylating the side chain, a rate-limiting step in the conversion of cholesterol into steroid hormones in the adrenal gland, [30] and its deficiency was associated with cellular degeneration and depressed steroidogenesis in the Leydig cells, [31] deficiency of Vitamin C in castrated rats was speculated to be responsible for the reduced extra-testicular testosterone and estradiol production despite an increase in cholesterol level.

Previous studies have established the fact that FSH promotes the production of steroid hormones from cholesterol by enhancing the cytochrome P-450 cholesterol side-chain cleavage enzyme (cytochrome P-450 scc ). [32] The castration-induced hypogonadism was followed by a slight increase in FSH concentration as a feedback mechanism to restore the plasma testosterone and estradiol concentration, probably from extra-testicular sites. Interestingly, Vitamin C supplementation caused increased testosterone and estradiol production in intact and castrated rats, but increased and reduced cholesterol level in the former and latter, respectively. This is suggestive of the fact that the insignificant effect of Vitamin C on FSH in intact rats limited the up-regulation of cytochrome P-450 scc in them, which hampered cholesterol catabolism in their adrenal gland. Furthermore, the increase in FSH concentration by Vitamin C in castrated rats might have led to up-regulation of the cytochrome P-450 scc enzyme as pointed out by the reduced cholesterol production, which could have favored the extra-testicular production of steroid hormone testosterone and estradiol. In other words, the Vitamin C-induced increase in testosterone and estradiol production in the intact rats could majorly be accounted for by the testicular source, and the process in the testis of intact rats might be less dependent on FSH-induced SCC of cholesterol. However, the Vitamin C-induced increase in the production of these steroid hormones in castrated rats could have been from extra-testicular sites which might be constantly making use of FSH-dependent cholesterol SCC.

While the majority of previous studies have given priority to the contribution of testosterone deficiency to the side-effects of castration in men, this study additionally suggests that estradiol deficiency equally plays an important role in castration-related side effects in males. This is similar to previous observation that castration is associated with multiple adverse effects, many of which are related to androgen as well as estrogen deficiency. [33] It has previously been shown that hypogonadism is prevalent in PCa patients undergoing ADT compared to those that undergo prostatectomy and/or radiation therapy or compared to age-matched controls. [34] Similarly, ADT-induced hypogonadism was reported to be responsible for the increased body mass index, increased fat mass, reduced lean body mass and muscle strength, and osteoporosis. Besides the desired physiological consequences of ADT in reducing serum androgens, castration is also associated with a decrease in circulating estrogens that are synthesized from androgens by peripheral aromatization. Despite having normal to elevated serum testosterone levels, men with congenital aromatase deficiency (and thus, nondetectable serum estrogen levels) have a high prevalence of osteoporosis, insulin resistance, and metabolic syndrome, [35] observation that underscores the importance of estrogens in men. Moreover, it is decreased estrogen rather than testosterone levels that are responsible for decreased bone density, accelerated rate of bone loss, and increased fracture incidence. [36] Thus, side effects induced by ADT leading to hot flashes, osteoporosis, metabolic syndrome, and higher cardiovascular events are related to androgen as well as estrogen deficiencies. [37] However, the relative contribution of testosterone and estrogen to these adverse effects remains unclear.


  Conclusion Top


This study showed that castration increases lipid profile and atherogenic risk in male rats. Moreover, these effects of castration are dependent not only on testosterone but also on estradiol. In addition, Vitamin C improves lipid profile and atherogenic risk in normal and castrated rats by increasing testosterone and estradiol production, possibly from extra-testicular sites. However, there is a need for further study to ascertain the actual site of the extra-testicular testosterone and estradiol production.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2]


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