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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 4  |  Issue : 1  |  Page : 6-12

Melatonin administration to castrated rats reversed the castration-induced dyslipidemia while potentiating increased testosterone production from other nontesticular sources


1 Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Kwara, Nigeria
2 Department of Physiology, School of Medicine and Pharmacy, University of Rwanda College of Medicine and Health Sciences, Huye, Republic of Rwanda, East Afrcia
3 Department of Anatomy, College of Health Sciences, University of Ilorin, Ilorin, Kwara, Nigeria

Date of Web Publication2-Jul-2018

Correspondence Address:
Dr. Abdullateef Isiaka Alagbonsi
Department of Physiology, School of Medicine and Pharmacy, University of Rwanda College of Medicine and Health Sciences, Huye
East Afrcia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njecp.njecp_1_16

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  Abstract 


Background: Castration has been shown to be associated with dyslipidemia. The present study aimed at investigating the effect of melatonin supplementation on castration-induced dyslipidemia. Materials and Methods: Twenty-five male Wistar rats were randomly divided into two surgical groups: Group I rats (n = 10) were sham-operated and then subdivided into 2 oral gavage treatment groups (n = 5 each) to receive either normal saline (1 ml/kg) or 10 mg/kg melatonin for 4 weeks. Group II rats (n = 15) were rendered bilaterally castrated and then subdivided into 3 oral gavage treatment groups (n = 5 each) to receive normal saline (1 ml/kg), 4 mg/kg melatonin, or 10 mg/kg melatonin for 4 weeks. Results: Castrated rats that received normal saline had reduced high-density lipoprotein (35.8 ± 3.8 vs. 62.37 ± 3.26 mg/dl), testosterone (0.30 ± 0.01 vs. 2.70 ± 0.20 ng/ml), estradiol (1.30 ± 0.01 vs. 2.70 ± 0.20 pg/ml) but increased low-density lipoprotein (57.90 ± 0.70 vs. 35.23 ± 0.93 mg/ml), triglycerides (158.20 ± 5.90 vs. 130.93 ± 2.96 mg/ml), total cholesterol (100.00 ± 1.70 vs. 73.67 ± 2.77 mg/ml), Castelli index (2.83 ± 0.35 vs. 1.19 ± 0.07), and had the same follicle stimulating hormone (3.86 ± 0.04 vs. 3.32 ± 0.17 mIU/ml) when compared to sham-operated rats that received normal saline, respectively. Melatonin supplements improved these parameters in normal and castrated rats, with 10 mg/kg melatonin-producing more noticeable effect. Conclusions: Melatonin administration to castrated rats reversed the castration-induced dyslipidemia while potentiating increased testosterone and estradiol production from other nontesticular sources.

Keywords: Atherogenesis, castration, lipid profile, melatonin, reproductive hormones


How to cite this article:
Olayaki LA, Alagbonsi AI, Adamson M, Ayodele OD, Olawepo A. Melatonin administration to castrated rats reversed the castration-induced dyslipidemia while potentiating increased testosterone production from other nontesticular sources. Niger J Exp Clin Biosci 2016;4:6-12

How to cite this URL:
Olayaki LA, Alagbonsi AI, Adamson M, Ayodele OD, Olawepo A. Melatonin administration to castrated rats reversed the castration-induced dyslipidemia while potentiating increased testosterone production from other nontesticular sources. Niger J Exp Clin Biosci [serial online] 2016 [cited 2018 Jul 19];4:6-12. Available from: http://www.njecbonline.org/text.asp?2016/4/1/6/235803




  Introduction Top


Previous reports on the role of testosterone in lipid homeostasis are controversial. Testosterone administration was reported to adversely affect lipoprotein metabolism including elevation of low-density lipoprotein cholesterol (LDL-C) and depression of high-density lipoprotein cholesterol (HDL-C),[1] in addition to the fact that men are also more prone to coronary heart disease (CHD) and possess higher risks of mortality from CHD than women.[2] Other authors have shown that endogenous testosterone is inversely related to the severity of carotid atherosclerosis as well as the incidence and severity of CHD in men.[3],[4] Furthermore, low testosterone is related to a number of metabolic disorders, such as insulin resistance,[5] type 2 diabetes mellitus (T2DM),[6] and metabolic syndrome (MetS),[7] which led to recommendation of testosterone replacement therapy (TRT) to ameliorate signs and symptoms of some metabolic and vascular diseases in middle-aged and elderly men with low serum testosterone.[8]

Since castration (a means of androgen deprivation) is one of the options in the management of prostate cancer, and is associated with dyslipidemia which is a risk factor for hypertension, T2DM, MetS, and CHD, study is needed to provide therapy that will reverse castration-induced dyslipidemia. Oxidation and inflammation are key components of atherogenesis,[9] and melatonin has been widely shown to have anti-oxidative and anti-inflammatory potentials,[10],[11] in addition to its well-reported positive effect on dyslipidemia.[12] The present study sought to investigate the role of melatonin supplementation in castration-induced dyslipidemia.


  Materials and Methods Top


Twenty-five male Wistar 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 our Institutional Ethics Committee.

Experimental protocol

After 2-weeks acclimatization to their new environment with standard laboratory diet and water given ad libitum, the 25 animals were randomly divided into two surgical groups: Group I rats (n = 10) were sham-operated and then subdivided into 2 oral treatment groups (n = 5 each) to receive either normal saline (1 ml/kg) or 10 mg/kg melatonin [13],[14] for 4 weeks. Group II rats (n = 15) were rendered bilaterally castrated and then subdivided into three oral treatment groups (n = 5 each) to receive normal saline (1 ml/kg), 4 mg/kg melatonin,[15],[16] or 10 mg/kg melatonin for 4 weeks.

Bilateral orchidectomy (surgical castration) was carried out as previously described.[17] 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. Our preliminary study shows that sham-operation had no effect on the studied parameters. Administration of freshly prepared drugs commenced a day after 1 week provided for the animals to fully recover from the surgery and was done by oral gavage between 9:00 and 10:00 am daily. Body weights of animals were monitored daily. Animals were sacrificed a day after the last treatment under ketamine anesthesia and plasma was collected from each animal and preserved at −20°C.

Estimation of lipid profile and hormones

The levels of HDL-C, LDL-C, triglycerides (TG), and total cholesterol (TC) were determined spectrophotometrically using microplate reader (Spectramax Plus; Molecular Devices, Sunnyvale, CA, USA) following the kit manufacturers' procedures. Atherogenic risk or Castelli index was calculated by dividing the TC by the HDL, both expressed in mg/dl.[18]

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 using SPSS version 16.0 for Windows (IBM Corporation, Armonk, NY, USA), followed by a post hoc least significant difference test for multiple comparisons. Data were presented as the mean ± standard error of mean. P ≤ 0.05 was considered statistically significant.


  Results Top


Effects of melatonin on lipid profile and Castelli index in sham-operated and castrated rats

The plasma HDL concentration was significantly lower in castrated rats that received normal saline (35.8 ± 3.8 mg/dl) than in sham-operated rats that received normal saline (62.37 ± 3.26 mg/dl) or 10 mg/kg melatonin (104.77 ± 2.41 mg/dl). The HDL in sham-operated rats that received 10 mg/kg melatonin (104.77 ± 2.41 mg/dl) was significantly higher than in sham-operated rats that received normal saline (62.37 ± 3.26 mg/dl). Similarly, the HDL in castrated rats that received 10 mg/kg melatonin (86.03 ± 0.47 mg/dl) and 4 mg/kg melatonin (72.08 ± 3.35 mg/dl) were significantly higher than in castrated rats that received normal saline (35.8 ± 3.80 mg/dl). In castrated rats, the increase in HDL caused by 10 mg/kg melatonin was more noticeable than the increase caused by 4 mg/kg melatonin [Table 1].
Table 1: Effects of melatonin on lipid profile in sham-operated and castrated rats

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The plasma LDL concentration was significantly higher in castrated rats that received normal saline (57.9 ± 0.7 mg/dl) than in sham-operated rats that received normal saline (35.23 ± 0.93 mg/dl) or 10 mg/kg melatonin (13.2 ± 1.35 mg/dl). The LDL in sham-operated rats that received 10 mg/kg melatonin (13.2 ± 1.35 mg/dl) was significantly lower than in sham-operated rats that received normal saline (35.23 ± 0.93 mg/dl). Similarly, the LDL in castrated rats that received 10 mg/kg melatonin (16.08 ± 2.84 mg/dl) and 4 mg/kg melatonin (18.93 ± 1.37 mg/dl) were significantly lower than in castrated rats that received normal saline (57.9 ± 0.70 mg/dl). In castrated rats, there was no significant difference in the LDL reduction caused by 10 mg/kg melatonin and 4 mg/kg melatonin [Table 1].

The plasma TG concentration was significantly higher in castrated rats that received normal saline (158.20 ± 5.9 mg/dl) than in sham-operated rats that received normal saline (130.93 ± 2.96 mg/dl) or 10 mg/kg melatonin (109.18 ± 4.98 mg/dl). The TG in sham-operated rats that received 10 mg/kg melatonin (109.18 ± 4.98 mg/dl) was significantly lower than in sham-operated rats that received normal saline (130.93 ± 2.96 mg/dl). Similarly, the TG in castrated rats that received 10 mg/kg melatonin (73.78 ± 2.21 mg/dl) and 4 mg/kg melatonin (115.35 ± 4.72 mg/dl) were significantly lower than in castrated rats that received normal saline (158.20 ± 5.90 mg/dl). In castrated rats, the decrease in TG caused by 10 mg/kg melatonin was more noticeable than the decrease caused by 4 mg/kg melatonin [Table 1].

The plasma TC concentration was significantly higher in castrated rats that received normal saline (100.00 ± 1.70 mg/dl) than in sham-operated rats that received normal saline (73.67 ± 2.77 mg/dl) or 10 mg/kg melatonin (92.60 ± 2.73 mg/dl). The TC in sham-operated rats that received 10 mg/kg melatonin (92.60 ± 2.73 mg/dl) was significantly higher than in sham-operated rats that received normal saline (73.67 ± 2.77 mg/dl). However, the TC in castrated rats that received 10 mg/kg melatonin (54.75 ± 1.53 mg/dl) and 4 mg/kg melatonin (76.65 ± 3.39 mg/dl) were significantly lower than in castrated rats that received normal saline (100.00 ± 1.70 mg/dl). In castrated rats, the decrease in TC caused by 10 mg/kg melatonin was more noticeable than the decrease caused by 4 mg/kg melatonin [Table 1].

The Castelli index (atherogenic risk) was significantly higher in castrated rats that received normal saline (2.83 ± 0.35) than in sham-operated rats that received normal saline (1.19 ± 0.07) or 10 mg/kg melatonin (0.89 ± 0.03). The atherogenic risk in sham-operated rats that received 10 mg/kg melatonin (0.89 ± 0.03) was significantly lower than in sham-operated rats that received normal saline (1.19 ± 0.07). Similarly, the atherogenic risk in castrated rats that received 10 mg/kg melatonin (0.64 ± 0.02) and 4 mg/kg melatonin (1.07 ± 0.07) were significantly lower than in castrated rats that received normal saline (2.83 ± 0.35). In castrated rats, the decrease in atherogenic risk caused by 10 mg/kg melatonin was more noticeable than the decrease caused by 4 mg/kg melatonin [Table 1].

Effects of melatonin on plasma reproductive hormones in sham-operated and castrated rats

The plasma testosterone concentration in castrated rats that received normal saline (0.30 ± 0.01 ng/ml) was significantly lower than in sham-operated rats that received normal saline (1.47 ± 0.09 ng/ml) or 10 mg/kg melatonin (4.78 ± 0.29 ng/ml). The testosterone in sham-operated rats that received 10 mg/kg melatonin (4.78 ± 0.29 ng/ml) was significantly higher than in sham-operated rats that received normal saline (1.47 ± 0.09 ng/ml). In castrated rats, 10 mg/kg melatonin (1.57 ± 0.13 ng/ml) but not 4 mg/kg melatonin (0.45 ± 0.15 ng/ml) caused significantly increased testosterone concentration when compared to normal saline (0.30 ± 0.01 ng/ml) [Figure 1].
Figure 1: Effects of melatonin on plasma testosterone concentration in sham-operated and castrated rats. Values are expressed as mean ± standard error of mean (n = 5). aP < 0.05 versus sham-operated + normal saline; bP < 0.05 versus sham-operated + 10 mg/kg melatonin; cP < 0.05 versus castrated + normal saline; dP < 0.05 versus castrated + 10 mg/kg melatonin

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The plasma estradiol concentration in castrated rats that received normal saline (1.30 ± 0.01 pg/ml) was significantly lower than in sham-operated rats that received normal saline (2.70 ± 0.20 pg/ml) or 10 mg/kg melatonin (4.05 ± 0.33 pg/ml). The estradiol in sham-operated rats that received 10 mg/kg melatonin (4.05 ± 0.33 pg/ml) was significantly higher than in sham-operated rats that received normal saline (2.70 ± 0.20 pg/ml). Similarly, the estradiol in castrated rats that received 10 mg/kg melatonin (5.78 ± 0.66 pg/ml) and 4 mg/kg melatonin (2.90 ± 0.29 pg/ml) were significantly higher than in castrated rats that received normal saline (1.30 ± 0.01 pg/ml). In castrated rats, the increase in estradiol caused by 10 mg/kg melatonin was more noticeable than the increase caused by 4 mg/kg melatonin [Figure 2].
Figure 2: Effects of melatonin on plasma estradiol concentration in sham-operated and castrated rats. Values are expressed as mean ± standard error of mean (n = 5). aP < 0.05 versus sham-operated + normal saline; bP < 0.05 versus sham-operated + 10 mg/kg melatonin; cP < 0.05 versus castrated + normal saline; dP < 0.05 versus castrated + 10 mg/kg melatonin

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There were no significant differences in the plasma FSH concentration in sham-operated rats that received normal saline (3.32 ± 0.17 mIU/ml) or 10 mg/kg melatonin (3.18 ± 0.09 mIU/ml) and castrated rats that received normal saline (3.86 ± 0.04 mIU/ml) or 4 mg/kg melatonin (3.53 ± 0.05 mIU/ml), while castrated rats that received 10 mg/kg melatonin (5.40 ± 0.55 mIU/ml) had significantly higher FSH than all of them [Figure 3].
Figure 3: Effects of melatonin on plasma follicle stimulating hormone concentration in sham-operated and castrated rats. Values are expressed as mean ± standard error of mean (n = 5). aP < 0.05 versus sham-operated + normal saline; bP < 0.05 versus sham-operated + 10 mg/kg melatonin; cP < 0.05 versus castrated + normal saline; dP < 0.05 versus castrated + 10 mg/kg melatonin

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  Discussion Top


The increase in lipid profile in castrated rats in the present study is in agreement with previous epidemiological studies which associated dyslipidemia to low testosterone in men.[19],[20] Since high lipid profile is a risk factor for various cardiovascular diseases, its high level in castrated rats might be linked to high mortality from cardiometabolic diseases observed in patients with prostate cancer undergoing different forms of androgen deprivation therapy which includes castration.

In addition to being a site of sperm production, the testes also serve as endocrine gland where hormones such as estrogen and testosteronel are produced in males. The seminiferous tubules in the testes are rich in germ cells that eventually differentiate into mature spermatozoa during the process of spermatogenesis, while the Leydig cells have endocrine potential to synthesize steroids (e.g., testosterone and estrogens) through the process of steroidogenesis. Both processes are under hypothalamic and hypophyseal control through their hormonal secretions that stimulate them. Since testosterone and estrogen are the major hormones secreted in the testes, we estimated the concentration of these hormones to ascertain if the castration-induced dyslipidemia and atherogenic risk is associated with deficiency of either or both of them.

Beyond testosterone, the impact of estrogen on male reproduction is of interest to andrologists since the latter is also produced from the former in the testis by an aromatase enzyme. In this study, castration not only caused a reduction in plasma testosterone concentration but also significantly reduced plasma estradiol concentration. This is an indication that castration in male is not only followed with testosterone depletion but also estrogen deficiency, and that the castration-induced dyslipidemia and atherogenic risk is not only testosterone-dependent but also estrogen dependent. It might also be a justification for the estrogen therapy received by males on different form of androgen deprivation to alleviate hot flushes [21] and improve bone mineral density [22] and lipid profiles.[23]

Previous reports on whether melatonin can treat atherosclerosis or not are controversial and inconclusive. For instance, supplementation of melatonin or its related compound, N-[2-(5-methoxy-1H-indol-3-yl) ethyl]-3,5-di-tert-butyl-4-hydroxybenzamide to an atherogenic diet in mice with genetic hypercholesterolemia, compared with melatonin-free mice, led to a spreading or no significant change in atherosclerotic lesions of the aorta, despite clear inhibition of lipoprotein oxidation by these substances in vitro.[24] Furthermore, ameliorative effects of melatonin on lipid profile in atherosclerosis and some disease conditions of MetS have been well reported.[25],[26] Contrarily, chronic melatonin administration to genetically hypercholesterolemic rats hindered the development of subendothelial fatty streaks formed by foam and mononuclear cells in the carotid artery, corresponding to an early stage of atherogenesis.[27] In humans, the majority of open trials reported improvement in lipid indices following treatment with melatonin, whereas the majority of placebo-controlled studies found no significant effect.[28] This ambiguity may be partly attributable to methodological limitations. However, melatonin administration in the present study caused significant improvement in the lipid profile and atherogenic risk in sham-operated and castrated rats.

Low levels of endogenous testosterone have been associated with an increased risk of atherosclerosis in men.[29],[30] Several clinical and epidemiological studies have reported that serum testosterone levels are inversely correlated with TC and LDL-C levels.[31],[32] Moreover, animal studies have also demonstrated markedly increased serum cholesterol levels in testosterone-deficient male mice.[33],[34] Testosterone deficiency is thought to promote atherosclerosis by modulating lipid metabolism.[35],[36] TRT was associated with a significant reduction of TG and an increase of HDL-C and was able to improve central obesity and glycometabolic control in patients with MetS and T2DM.[37] Other studies observed no relationship between TRT and lipid profile, although some even reported unfavorable effects of TRT on serum lipids.[38],[39] In the present study, castration-induced dyslipidemia associated with reduction in testosterone and estradiol, and the concurrent restoration of these parameters by melatonin not only show its potency in ameliorating castration-induced dyslipidemia but also support the contention that testosterone and estradiol play a beneficial role in atherogenesis.

Since testosterone and estradiol are mostly produced from the testis, the increase in plasma concentration of these hormones in castrated rats treated with melatonin was surprising and of interest to us. Previous studies have shown the possibility of extratesticular testosterone and androstenedione production from the adrenal gland, liver, kidney, and gastroduodenal tract of bilaterally orchidectomized patients.[40],[41] It is thus speculated that the increased testosterone and estradiol production elicited by melatonin in castrated rats might have been from any of the extratesticular sources that need to be further determined.

Melatonin has been shown to be positively correlated with plasma testosterone concentration [42],[43] and possess anti-oxidative and anti-inflammatory potentials.[10],[11] However, further studies are also needed to substantiate if the ameliorative effect of melatonin on castration-induced dyslipidemia is mediated by its anti-oxidative, anti-inflammatory, or testosterone-enhancing potential. Moreover, the actual site of the extra-testicular testosterone and estradiol production elicited by melatonin in castrated rats should be further investigated.


  Conclusions Top


This study showed that castration increases lipid profile and reduces plasma testosterone and estradiol concentrations. In addition, melatonin administration to castrated rats reversed the castration-induced dyslipidemia while potentiating increased testosterone and estradiol production from other nontesticular sources.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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