الفهرس 
Androgens and androgen deprived state
AnimalsOnly 14 pages are availabe for public view
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Abstract
The present work was planned to assess the vascular functions in androgen-deprived state induced by orchidectomy and the mechanisms of control of arterial blood pressure. The study included the assessment of baroreceptor sensitivity and the vascular reactivity of aortic ring smooth muscle to clarify the exact mechanism(s) of vascular dysfunction. Also, androgen deprivation by finasteride treatment was studied for the associated cardiovascular risk factors.
I-Androgen-deprived state induced by surgical orchidectomy
This was performed on 55 adult male Wistar rats that were classified to orchidectomized rats subjected to androgen deprivation through surgical orchidectomy (ORX, n=28) and their sham-operated controls (n=27). Surgical orchidectomy was achieved by bilateral removal of testes and studied after 4 weeks
Surgical orchidectomized rats and their sham-operated controls were subjected to recording of ECG, measurement of arterial blood pressure, and invivo studying of baroreflex functions and their responses to pressor and depressor agents, phenylephrine (PE) and sodium nitroprusside (SNP) respectively. Thereafter, vascular reactivity was studied invitro using isolated aortic rings to determine their contractile and relaxant responses to vasoactive agents, PE and acetylcholine (ACh). Plasma total testosterone, free testosterone and dihydrotestosterone were estimated. In addition, plasma antioxidant catalase (CAT) enzyme activity and the pro-oxidant malondialdhyde (MDA) were measured. Nitrate, the metabolic product of nitric oxide (NO) was assayed in aortic tissue.
The results revealed significant reduction in the plasma levels of total testosterone, free testosterone, dihydrotestosterone levels and dihydrotestosterone: testosterone ratio in the orchidectomized rats when compared to their sham-operated controls. This was associated by significant increase in the final body weight, final body mass index and their percentage change in the orchidectomized rats compared to the sham-operated control reflecting the role of testosterone as a potent inhibitor for fat cells to store lipids.
ECG study showed significant increase in the heart rate as well as significant prolongation in the QRS duration in the orchidectomized group compared to the sham-operated control group while insignificant differences existed between both groups regarding the other parameters (R wave voltage, P-R interval, Q-To interval and Q-Tc interval). These data shows that androgen-deprivation may be a predisposing factor for development of cardiac arrhythmias.
Baseline systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and heart rate were insignificantly different between the orchidectomized (ORX) and the sham operated control groups in any of the studied parameters. In the androgen-deprived rats, the pressor responses to phenylephrine (PE) and the depressor responses to sodium nitruprusside (SNP) were not significantly different from sham-operated controls, the SBP remained higher in the orchidectomized rats than in sham-operated rats, though insignificant. The SBP& DBP pressor responses to PE sequential doses were higher in the orchidectomized rats than the sham-operated controls, though insignificant allthrough except in the DBP pressor response and delta change in response to 5µg/kg PE which demonstrated statistically significantly increased pressor response in orchidectomized group of rats.
These findings reflect attenuated baroreflex vagal limb and a tendency toward a pro-hypertensive state in orchidectomized rats especially in cases of stress. The baroreflex sensitivity (vagal limb) in ORX rats was depressed compared to baroreflex sensitivity in intact animals, confirming the role of testosterone in enhancing baroreflex bradycardia.
Significant decrease in the aortic ring response to phenylephrine was observed in the orchidectomized ones compared to sham operated control rats, while aortic segments response to ACh was insignificantly higher in ORX than in sham-operated control group, yet the ACh/ PE ratio, was significantly increased in ORX rats.
Biochemical studies revealed significant decrease in the plasma catalase activity accompanied by significant increase in the malondialdhyde level in the orchidectomized rats when compared to the sham-operated control rats, in addition, significant decrease in aortic tissue nitrate was also present.
The combined decreased contractile response to PE and the increased relaxing response to ACh in the form of increased ACh / PE ratio, in presence of significant decrease in NO are evidences that the vasorelaxing response overweighs the vasoconstrictor response in the aortic segments isolated from androgen-deprived rats. Moreover, the significant decrease in aortic tissue nitrate could be accounted for by the increased oxidative stress induced by androgen deprivation.
II-Androgen-deprived state induced by Finasteride treatment
This study was performed on 34 adult male Wistar rats. Rats were classified to Finasteride-treated group (n=17), and vehicle-treated group (n=17). Finasteride is a specific potent competitive inhibitor for the 5α-reductase enzyme which is responsible for the conversion of testosterone to dihydrotestosterone. The drug was dissolved in 1 % gum acacia and given orally by gavage in a dose of 10mg/kg for 10 successive days.
Finasteride-treated group and their controls were also subjected to recording of ECG, measurement of arterial blood pressure using animal rat tail sphygmomanometer. Plasma total testosterone, free testosterone, dihydrotestosterone, plasma antioxidant catalase (CAT) enzyme activity and the pro-oxidant malondialdhyde (MDA) were estimated. In addition, estimation of plasma triglycerides, total cholesterol, high density lipoprotein-cholesterol (HDL-c) and low density lipoprotein-cholesterol (LDL-c) was done. Cardiac weights whether absolute or relative to body weights were determined.
Finasteride treatment resulted in significant marked reduction in the plasma dihydrotestosterone level, dihydrotestosterone: total testosterone ratio in the finasteride-treated rats; associated with reduction in the total plasma testosterone level which was less marked though significant, while the free testosterone and its ratio to total testosterone were slightly different and insignificant in the finasteride-treated group of rats.
ECG results showed no significant difference regarding heart rate, R wave voltage, P-R interval and QRS duration between the finasteride-treated rats and the vehicle-treated control rats, however, the observed Q-T interval (Q-To interval) and the corrected Q-T interval (Q-Tc interval) were significantly shortened in the finasteride-treated group compared to the vehicle-treated control group.
Insignificant differences in SBP, DBP and MABP between finasteride-treated group and vehicle controls. Also, the absolute cardiac weights as well as relative cardiac weights were not different in the two groups. These data may exclude finasteride treatment as a risk factor for the development of hypertension and/ or left ventricular hypertrophy
Biochemical studies revealed no significant differences in the plasma catalase activity and malondialdhyde levels between both groups, meanwhile, significant reduction in the levels of plasma triglycerides, plasma total cholesterol, low density lipoprotein-cholesterol and atherogenic index in the finasteride-treated rats in comparison to the vehicle-treated control rats. This was accompanied by significant increase in the plasma high density lipoprotein-cholesterol in the finasteride treated group.
These data point to that finasteride treatment has antiatherogenic effects, suggesting that dihydrotestosterone, has exacerbating effects on atherosclerosis risk factors including plasma triglycerides, total cholesterol and LDL-c, and, depressing effects on HDL-c, the protective factor against atherosclerosis.
from the findings of the present study, it may be concluded that hypogonadal state has a limited safety margin, and deterioration in cardiac and vascular functions in the absence of male sex hormones may occur, thereby suggesting protective effects of androgens on the cardiovascular system.
In addition, low testosterone level may be a component of a multidimensional metabolic syndrome with underlying risk factors for the development of obesity, type 2 diabetes mellitus, hypertension, dyslipedemia and oxidative stress.
Therefore, it could be assumed that, provided there is no contraindication such as cancer prostate, testosterone replacement therapy is to be considered for treatment of hypogonadal men especially those with risk factors for coronary vascular disease.
Some studies suggest that testosterone therapy is beneficial to the cardiovascular system and that low levels of testosterone negatively affected the cardiovascular system (Araujo et al., 2011; Ohlsson et al., 2011). On the other hand, other studies suggest that exogenous testosterone was associated with an increase in the adverse effects in elderly men ( Basaria et al., 2010). Thus, the effects of testosterone replacement therapy in such conditions remain a point of controversy and is candidate for further research.