Gonadal Responses to Antipsychotic Drugs

[Full title: Gonadal Responses to Antipsychotic Drugs: Chlorpromazine and Thioridazine Reversibly Suppress Testicular Functions in Albino Rats]

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Life International Journal of Pharmacology ISSN 1811-7775 Life science alert ansinet Asian Network for Scientific Information

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International Journal of Pharmacology 1 (3): 287-292, 2005 ISSN 1811-7775 2005 Asian Network for Scientific Information Gonadal Responses to Antipsychotic Drugs: Chlorpromazine and Thioridazine Reversibly Suppress Testicular Functions in Albino Rats Y. Raji. 'S.. Ifabunmi, O.S. Akinsomisoye, A.). Morakinyo and 'A.K. Oloyo Department of Physiology, College of Medicine, University of Ibadan. Ladoke Akintola University of Technology, Ogbomoso, Obafemi Awolowo University, Ile-Ife, Nigeria Abstract: This work was undertaken to investigate the individual effects and probable mechanism of action of chlorpromazine hydrochloride (largactil) and thioridazine hydrochloride (melleril) on male reproductive functions, in albino rals. A total of 45 adult male albino Wistar-strain rals were used. Five rals served as the control while the remaining forty rats were divided into four groups, of 10 rats each. Rats in group I were treated with 2.3 mg kg BW, while those of group II received 5.7 mg kg BW of chlorpromazine. Rats in group III. were treated with 1.7 mg kg BW, while those of group IV received 2.3 mg kg BW of thioridazine. Control rats received vehicle of the drugs (i.e. distilled water). Drugs and vehicle were administered orally on a daily basis. Five rals, in each of the four drug-treated groups served as the recovery rals. Sperm characteristics evaluation, serum levels of testosterone and histopathological alterations in the testis were assessed both after four weeks of continuous drug administrations and four weeks of drug withdrawal. Chlorpromazine and thioridazine significantly caused a reduction in the absolute weights of the testis, epididymis and seminal vesicles (p<0.01) at high and low doses. Weight of the prostate gland was also reduced significantly (p<0.05) at the high dose. The epididymal sperm motility, viability (life/death ratio) and counts were significantly reduced (p<0.01) at high dose of chlorpromazine and thioridazine. Moreover, sperm morphological abnormalities were significantly increased (p<0.01) at both doses of the drugs. Reduction in serum levels of testosterone for both drugs was statistically significant (p<0.01). The histopathological alterations observed in the testis includes moderate to severe degeneration of seminiferous tubular epithelium. Fertility and other associated changes were restored within four weeks of cessation of treatment. Chlorpromazine and thioridazine appear to have reversible antifertility actions in male albino rats. These actions were probably mediated within the testis and epididymis. Key words: Antipsychotic, reproduction, sperm, testosterone, fertility INTRODUCTION Antipsychotic drugs are central nervous system (CNS)-influencing drugs that are used in most psychiatric hospitals to real people with mental disorders. Chlorpromazine and thioridazine. of the class phenothiazines are the commonly used ones. Phenothiazines have been used mainly for the realment. of schizophrenia but are also effective in some other psychoses¹¹ Chlorpromazine and thioridazine were originally developed as antihistamiine and antihypertensive agents However, fortuitous observations of their calming properties led to their trial in psychiatric patients. The antipsychotic drugs generally have the antiemetic. antinausea, analgesic, sedatives and general anaesthetic effects. Several studies have shown that the central nervous system influencing drugs do have adverse effects on male reproductive functions Phenothiazines are known to cause hyperprolactinaemia leading to animenorrhea, ccasation of normal cyclic ovarian function, loss of libido occasional hirsutism and long-term risk of osteoporosis in women. The effects of hyperprolactinemia induced by antipsychotic drugs in men are impotence, loss of libido and hypospermatogenesis. The main mechanism of action of these drugs on reproduction is by blocking dopamine receptors and also by increasing the conversion of androgens to estrogens thereby elevating the plasma levels of the latter hormone. It is however nol. known whether these effects can lead to alterations in male reproductive efficiency sufficient to cause male infertility. The present study was therefore designed to investigate the individual effects of chlorpromazine Corresponding Author: Y. Raji, Department of Physiology. College of Medicine, University of Ibadan, Ibadan, Nigeria E-mail: raji ui@yahoo.com or yoraji@yahoo.com 287

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Intl. J. Pharmacol., 1 (3): 287-292, 2005 hydrochloride and thioridazine hydrochloride (largaclil and melleril, respectively) and their probable mechanism of action on male reproductive functions in albino rats. MATERIALS AND METHODS Animals: Adult male Wistar-strain albino rats (180-200 g) obtained from the central animal house, College of Medicine, University of Thadan, were used for the study. These animals were maintained and housed under standard laboratory conditions (temperature, 27°C and lighting, about 12 h/day) and they were fed with standard rat diet (Ladokun Feeds Nig. Ltd-Ibadan) and water ad libition. A total of 45 adult male rats were used. 5 rats served as the control group and the remaining rats were divided into four equal groups of ten rats each and treated as indicated in the study protocol. Drug and study protocol: Chlorpromazine hydrochloride (Hawgreen Ltd, Dublin) and thioridazine hydrochloride (Norvatis Pharmaceuticals, UK) were used in this study. Different concentrations of these drugs were prepared by dissolving known milligrams in a known volume of distilled water, based on comparison between the human dosage and body weights of the animals. Group I rats received 2.3 mg kg BW of chlorpromazine, while group Il rats received 5.7 mg kg¹BW of chlorpromazine. Rats in group III received 1.7 mg kg BW of thioridazine, while those in group IV were treated with 2.3 mg kg BW of thioridazine. Control rats received distilled water, which was the vehicle for the drugs. Daily administration of drugs and vehicle was done intragastrically for four weeks using oral cannula. 5 rals from each drug-treated group were kept for additional four weeks to recover after the last treatment was given. All rats were weighed weekly. Autopsy: Animals were weighed and autopsied under ether anesthesia 24 h after last dosing. Blood was collected from each animal via cardiac puncture from which serum used for testosterone assay was obtained. The remains of the rats were cul open and the liver, heart, kidneys, testes, seminal vesicles, prostate gland and epididymis were removed and weighed separately. Epididymal sperm motility and sperm counts: Epididymal spen motility was assessed immediately the rats were autopsied. Sperm progressive motility was determined by conventional methods and the number of motile spermatozoa were calculated per unit area and expressed as percentage motility. Sperm counts were done using a haemocytometer and the results were expressed as million/ml of semen suspension. Viability and morphological studies: Viability study was done by preparing a uniform smear of the spermatozoa on slides with Eosin Nigrosin stain. Hundred sperm cells were counted per slide, in order to obtain the percentage of live/death ratio. Morphological aberrations of abnormal spermatozoa were determined from a total count. of 400 spermatozoa, in smears obtained with Eosin/Nigrosin stain and smear made with Wall and Ewas stain. Abnormal spermatozoa were observed under the microscope, using X 100 objective under immersion oil. Sperm abnormalities were classified, as described by Blooms. Analysis of serum levels of testosterone: Serun testosterone concentrations were determined with the tube-based enzyme immunoassay (ELA) method. The ELA Testosterone kil was obtained from the Nzemal. (Nig) Limited, Akoka-Yaba, Lagos. The kit was manufactured in United Kingdom by Immunometrics (UK) Ltd. This method meets the WHO standards and is part of its programme for research in human reproduction. The within assay variation was 8.1% and the sensitivity was 0.3 ng mL. The optical density was read by using a spectrophotometer that was sensitive at wavelengths of between 492 al 5.50 T. Testicular histology: This was carried out as carlier described Briefly, the testes were fixed in 10% formal saline immediately after weighing. The preserved testes were then passed through the routine laboratory histological procedures and slides were stained with haematoxylin and cosin. Statistical analysis: Data in text and tables are presented as mean standard error of the mean (SEM). Statistical significance between groups was determined using student "t" test and ANOVA where appropriate.... RESULTS Body and organ weights of rats treated with chlorpromazine and thioridazine hydrochloride: There was a significant increase in the absolute body weights of drug treated rats (p<0.05) when compared with their control counterparts (Table 1 and 2). There was also a significant decline in the weights of the testis, epididymis and seminal vesicles (p<0.01) when compared with their control counterparts (Table 1 and 2). The reduction, in weights of prostate gland was significant (p<0.05) at the high dose of the drugs. During the recovery period, there was a gradual increase in weight of the testis and epididymis towards the normal control values. 288

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Intl. J. Pharmacol., 1 (3): 287-292, 2005 Table 1: Absolute Organ weight and Final % difference in body weight of Chlorpromazine-treated male rats Values are expressed as mean-s.em for s Treatement Final % differenICE group Control in body weight 1144.912.8 (+144.942.7) Testis (g) 1.4410.02 Adrenal gland Epididymis 0.02710.09 0.4510.01 Sambal vesicle (g) 0.99 10.01 2.3mg kg BW Chlorpromazine +155.3±3.9 (1160.543.3) 5.7mg kg BW Chlorpromazine +134.7±2.5 (+160.4+2.8) (1.46+0.02) 1.13±0.04* (1.2 110.02) 0.93±0.06" (1.01+0.11)* (0.027+0.05) 0.020±0.01 (0.02210.01) 0.010±0.03 (0.023+0.01) (0.45+0.01) 0.33±0.009* (0.99+0.01) Prostate gland (G) 0.32L0.02 (0.32+0.02) 0.77±0.02 0.26±0.02 (0.038 0.03)* (0.9710.01) (0.3310.02) 0.24+0.02 0.19±0.02" (0.23+0.02) 0.75±0.03 (0.91+0.02) (0.30+0.006) Table 2: Absolute Organ weight and Final difference in body weight of Thioridazine-treated male rats. Values are expressed as mean+s.e.mn for n 5 Treatement Final % difference group in body weight 11/11.812.8 Testis (g) Adrenal gland Epididymis 0.1510.01 Prostate gland (G) Seminal vesicle (g) (0.045 0.001) 0.25+0.002** 0.99 10.01 (0.99±0.01) 0.321 0.02 (0.32+0.02) 0.76+0.02** Control 1.7mg kg BW Thioridazine 2.3mg kg TW Thioridazine (+144.7±2.8) +156.3+4.1 (+155.43.8) 1161.412.5 (+160.1+2.3) 1.41411002 (1.44±0.02) 0.96-002** (1.11±0.02)* 0.59 0.050 (0.83+0.03)* 0.02710.0009 (0.027±0.09) 0.020+0.001 (0.025±0.001) 0.022.10.001 (0.024+0.001) (0.33±0.01)** 0.161001 (0.25*+0.01)* (0.96±0.02) 0.73 1001 (0.96+0.01) 0.26+0.08 (0.31+0.02) 0.221 0.009 (0.294-0.005) *Significantly different from the contral (p<0.01). |= Gain in body weight-Loss in body weight. Values presented in parenthesis show recovery experiment. valuc Table 3: Effect of chlorpromazine and thioridazine on sperm characteristics Treatment group % Motility %Viability (Life' death) Epididymal sperm count (10/m Control 97.80+0.20 (95.80±0.20) 98.00 10.10 (916.00±0.20) 6.96+0.50 (6.86±0.10) Results are presented as Mean+SEM (115) Chlorpromazine (2.3mg/kgBW) 76.00-1.88* (93.00=1.221* 81.80 1.16* (96.20-0.73)" Chlorpromazine (5.7mg/kgBW) 38.00-3.74* (84.00=2.45)* 56.60 3.61* (54.20-0.97)" 4.52-0.15* 5.020+0.14* (6.50=0.5-1) (1.51-0.09)* Statistically significant *(p<0.01) 35 Drug treated groups Thioridazine (1.7mg/kgBW) 77.00+2.00* (91.00±1.87)" 89.10 +0.87* (95.20+1.46) 4.93+0.07** (5.90±0.85) Thioridazine (2.3mg kg 'TW) 53.00+1.22* (87.00±1.26)** 70.2011.39* (34.00±1.00) 3.50+0.08* (5.22±0.53)** **(p<0.05)Values presented in parenthesis show recovery experiment value Recovery groups 30 25- 20Percentage sperm abnormality (%) 15- 10- 4 5 0 Control 2.3 mg/kg chlor 5.7 mg/kg chlor 1.7 mg/kg thior 2.3 mg/kg thior Drug treatment groups Fig. 1: Effect of chlorpromazine and thioridazine on morphological characteristics of sperm in albino rats Effects of chlorpromazine and thioridazine hydrochloride on sperm functions in rats: Table 3 and 4show the effects of chlorpromazine and thioridazine on sperm functions in rats, after 4 weeks of treatment and subsequent four weeks of recovery. The spenu motility was significantly reduced (p<0.01) when compared with the controls, in 289 both doses of the drugs. The qualitative motility was gradually affected which led to complete regression of motility after 1 weeks of treatments. The reduction in sperm motility was accompanied by significant (p<0.01) dose-dependent increase in morphological defects. (Fig. 1). The most common abnormality encountered for

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Serum testosterone level (m mol L ') 6 Intl. J. Pharmacol., 1 (3): 287-292, 2005 Drug treated groups Recovery groups 0 Control 2.3 mg/kg chlor 5.7 mg/kg chlor 1.7 mg/kg thior 2.3 mg/kg thior Drug treatment groups Fig. 2: Effect of chlorpromazine and thioridazine on serum levels of testosterone in male albino rats Table 4: Histologic scores of the lestes Chlorpromazine and Thioridazine Fry drochloride treated rats Treatment Seminiferous tubule degeneration Oederna/vascular congestion Control (Recovery) Chlorpromazine 2.3 mg kg b.w | | (Recovery) I 5.7 mg kg 'b.w ||| (Recovery) Thioridazine 1.7 mg kg 'b.w | | (Recovery) 2.3 mg kg 'h.w | | (Recovery) Genn cell necrosis || || Key to scores: == Absence of abnormal histologic features, Vild abnormal histologic features, Moderately severe histologic abnormality; ||=Severe histologic abnormality epididymal sperm was simple bent tail (about 60%). However, the sperm motility gradually increased during the recovery period. There was also a decrease in sperm abnormalities in the recovery groups. The decrease in epididymal sperm counts in response to cach of the drugs was significantly (p<0.01) different from the control (Table 3). In the recovery group, the epididymal sperm counts for both drugs were significantly increased (p<0.05) only at the high dose group. However there was no significant change in this parameter at a low dose (Table 3). Similarly, the viability of spermatozoa (i.e. percentage live) was significantly reduced in both drugs. The reduction in sperm viability in both doses was also significantly different from controls. In the recovery groups the percentage live spermatozoa was significantly increased (p<0.001) only at high dose of the drugs, when compared with the controls. Effects of chlorpromazine and thioridazine hydrochloride on serum testosterone levels: There were dose-dependent decreases in serum testosterone levels in chlorpromazine and thioridazine treated rats. This reduction was highest for the high dose (p<0.01) and lowest for the low dose (p<0.01) of each of the two drugs (Fig. 2). Histology of rat testis treated with chlorpromazine and thioridazine hydrochloride: As shown in Table 4, the control group exhibited normal testicular histology, with evidence of spermatogenesis, whereas there were germ cell necrosis, oedema (vascular congestions) and dosedependent increase in seminiferous tubular degeneration in groups that were treated with cach of the drugs. There was however some evidence of regenerative changes with some disorganization and a few tubules (containing mature spermatozoa) still visible in the recovery groups. DISCUSSION The results suggest that chlorpromazine and thioridazine could cause reversible reproductive impairment in male albino rats. Chlorpromazine and thioridazine are antipsychotic drugs that are known to have anaesthetic effects; they produce a loss of consciousness and a tendency to sleep In humans they may increase weight by stimulating appetite. 290

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Intl. J. Pharmacol., 1 (3): 287-292, 2005 Ti has been reported that a change in either absolute or relative weight of an organ after administering a chemical is an indication of the toxic effect of the chemical. The observed change in relative weight of the testes and other accessory reproductive organs in our study indicate that chlorpromazine and thioridazine might be toxic to these organs at least during the period of treatments. Consequently the reductions in the weights of the testis, epididymis, seminal vesicle and prostate gland could not be uncommected with the sensitivity of these organs to these drugs in vivo. These dugs have been reported to have the ability to permeate the biomembrane barriers of most reproductive organs. However, the weights of the kidney, heart, liver and adrenal glands were not affected, both during the drug administration and recovery periods suggesting that they are not toxic to these organs. The decrease in weights of the testis. epididymis, seminal vesicle and prostate gland, were accompanied by a decline in sperm motility, sperm counts and viability, in chlorpromazine and thioridazine-treated rats. The decline in percentage viability of the sperm could be correlated with the reduction in sperm motility, since non-motile spermatozoa were usually considered dead and could not be counted as live spermatozoa. The viability was significantly increased in the recovery group. Moreover, the decline in epidydimal spent counts in response to the drugs, might be due to a direct effect of these drugs on the epididymal site probably by acting as a spermatoxic agent. This finding agrees with carlier reports that the maturational events of spermatozoa taking place in the epididymis are vulnerable to chemical interference[1] It is important to note that a significant decline in scnim levels of testosterone was observed 117 chlorpromazine and thioridazine treated rals when compared with the controls in this study. The observed effects of these drugs on reproductive organs appear therefore to be partly mediated by alteration in circulating androgen levels. This alteration in the hormonal milieu of male albino rats was dose-dependent and consistent with the report that antipsychotic drugs produce striking adverse effects on reproductive system. The drugs are known to decrease libido and cause gynecomastia in males while ammenorrhea. galactorrhea and false-positive pregnancy tests and increase libido are common side effects in females. Phenothiazines (chlorpromazine and thioridazine) block dopamine receptors resulting in hyperprolactinemia. These actions appear to be nonspecific for phenothiazines since there is high prevalence of sexual dysfunction in men and women treated with neuroleptic drugs. They have also been reported to increase peripheral conversion of androgens lo estrogens. This is in agreement with the increased concentration of estrogen carlier reported Women undergoing antipsychotic drug treatment displayed significantly lower levels of estradiol and progesterone, whereas in men, the levels of free testosterone and DHEA-S were significantly lower than in controls. This mechanism of action of phenothiazines supports the significant reduction in serum levels of testosterone observed in the present study. It is also possible that the normal negative feedback control of secretions of gonadotrophin releasing homione from the hypothalamus and /or gonadotrophins especially luteinizing hormone from the adenohypophysis was adversely affected in view of their adverse effect on Lestosterone secretion. The hypothalamic nervous pathways that control the secretion of gonadotrophins are inhibited by CNS-influencing drugs such as marijuana, the narcotics, barbiturates and tranquilizers, making these pathway a major mechanism for the effects of drugs on reproductive hormones Moreover Soliman et al. ¨³1 reported male antifertility effects of antiepileptic drugs, carbamazepine and sodium valproate in rats. These authors reported significant. decrease in plasma testosterone, FSH and LH and an increase in prolactin levels in rats treated with the drugs. After four weeks of recovery period, the serum Lestosterone remained at low levels al were similar to those of the rals, which were not. allowed a recovery. period. This is consistent with the report of Daniel et al.[20] on the pharmacokinetics of thioridazine in rats. According to their study, chronic treatment of male rats with thioridazine produced significant increases in the plasma concentrations of the parent compound and its metabolites, which were accompanied, with prolongation of their plasma half-lives. Similar effects are likely with other phenothiazines including chlorpromazine. This probably indicates that the effect of these drugs on testosterone secreting cells (Leydig cells) in rats persisted beyond this period. Thus, a more prolonged recovery period would be required for full restoration of normal testosterone secretion in the treated rats. The reduction in sperm counts, motility and viability and significant increase in sperm abnormalities were accompanied with changes in testicular histology in this study which could be induced by alterations in steroid synthetic capacity of Leydig cells. There were visible lesions in the testis of the treated rats when compared to the control (Table 4). Congestions of blood vessels and degeneration of the seminiferous tubules, which could lead to inhibition of spermatogenesis, were also observed. At higher concentrations of the drugs, the seminiferous tubular degeneration appeared more severe indicating that the drugs produced deleterious effects on the testis. Although prolactin concentration was not measured in 291

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Intl. J. Pharmacol., 1 (3): 287-292, 2005 the present study, it is possible that hyperprolactinemia. was induced by the significant increase in estrogens secretion. The increased estrogens secretion could form the basis for the disorganization of the cytoarchitecture of the testes Measurement of FSH, LH, GnRH and prolactin levels and possibly enzymes involved in the conversion of androgens to estrogens might throw more light into the probable mode of antireproductive effects of these drugs and could facilitate efforts at reducing the reproductive side effects of these drugs. 1 2. 3. 4. 5. G. 7. 8. 9. REFERENCES Hollister, L.E., 1995. Antipsychotic and Lithium in Basic and Clinical Pharmacology by Katzung, B.G. (6th Edn.), pp: 433-447. Scaramuzzi, R.J., J.A. Downing, S. Williamson and J. Poll. 1997. The circulating concentration of FSH LH and Prolactin in the questradiol-Implanted ovariectomised ewe treated with caffeine. Animal Reproduction Sci., 45: 273-282. Soliman, G.A. and Abla AbdEl- Megind, 1999. The effect of antipsychotic drugs-carbamazepine and sodium valproate on fertility of male rats. DTW-Deutische Tierazithchue Wochenseechift, 106: 110-113. Pelly, R.G., 1999. Prolactin and antipsychotic medications: Mechanism of action. Schizophrenia Res., 35: S67-873. Zemjanis, R. 1970. Collection and evaluation of semen. In Diagnostic and Therapeutic Technique in Animal Reproduction 2nd Edn., The Williams and Wilkikins Comp. Baltimore. World Health Organisation, 1985. WHO Laboratory Manual for Examination of Human Semen and Semen-cervical Mucus Interaction 2nd Edn., Cambridge University Press. Raji, Y., U.S. Udoh, 0.0. Mewoycka, F.C. Ononye and A.F. Bolarinwa, 2003. Tuplication of reproductive endocrine malfunction in male antifertility efficacy of Azadirachta indica extract in rats. Afr. J. Med. Med. Sci., 32: 159-165. Bloom, E., 1972. The ultra structure of some characteristic sperm defects and a proposal for a new classification of bull spermiogram. Ahi del VII Symposia International de Zootechia Milano, Pp: 125-139. Bloom, E. 1973. The Ultra structure of some characteristic sperm defects. Nord Vet. Med., 25: 283-287. 10. Snedecor, G.W. and W.G. Cochran, 1980. Statistical Method 7th Edi, Aness Iowa State University. pp: 215. 11. Baldessarini, R.J., 1980. Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders. III: Goodman and Gilman's Pharmacological Basis of Therapeutics (Ed.) MacMillan Pub. Co. Inc. New York, pp: 301-417. 12. Simmons, J.E., R.S.H. Yang and E. Berman, 1995. Evaluation of the nephrotoxicity of complex mixtures containing organics and metals: Advantages and disadvantages of the use of real-world complex mixtures. Environ. Health Perspect, 103 Suppl. 1: 67-71. 13. Orgebin-Christ, M.C., B.J. Denzo and J. Davier, 1975. In: Iland Book of Physiology. Sect 7, Vol. V. Halmilton, D.W. and R.O. Greeps (Eds.), Am. Physiol. Sec. Washington D.C., pp: 319-338. 11. Mitchell, J.E. and M.K. Popkin, 1982. Antipsychotic drug therapy and sexual dysfunction in men. Am. J. Psychiatry, 139: 633-637. 15. Nishikawa, T., M. Tanaka, I. Koga and Y. Uchida, 1985. Prophylatic effects of neuroleptics in symptom-free schizophrenics: Role of dopaminergic and noradrenergic blockers. Biol. Psychiatry, 20: 1161-1166. 16. Ghadirian, A.M., G. Chouinard and L. Armable, 1982. Sexual dysfunction and plasma prolactin levels in neuroleptic-treated outpatients. J. New. Men. Dis. 170: 463-467. 17. Baptista. T., D. Reyes and L. Hemandez, 1999. Antipsychotic drugs and reproductive hormones: Relationship to body weight regulation. Pharmacol. Biochem. Behav. 62: 409-417. 18. Smith. C.G. and R.H. Asch, 1987. Drug abuse and reproduction. Fert. Sterility. 18: 355-373. 19. Greenfield S.F. and C. O'leary, 1999. Sex differences in marijuana use in the United States. Harvard Rev. Psychiatry, 6: 297-303. 20. Daniel, W.A., M. Syrek, A. Mach, J. Wojoikowski and J. Boksa, 1997. Pharmakokinetics of thioridazine and its metabolites in blood plasma and the brain of rals after acute and chronic realment. Polish J. Pharmacol., 19: 139-152. 21. Gill-Sharma, M.K., N. Balasinor and P. Parte, 2001. Effect of intermittent treatment with tamoxifen on reproduction in male rats. Asian J. Androl., 3: 115-119. 292

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Mental disorder, Loss of consciousness, Adverse effect, Central nervous system, Statistical analysis, Relative weight, Fertility, Sedative, Sexual dysfunction, Statistical Significance, Sperm motility, Sperm count, Sperm viability, Drug administration, Antifertility effect, Optical density, Spermatogenesis, Luteinizing hormone, Wistar strain albino rats, ANOVA, Significant increase, Wistar strain, Male infertility, Recovery period, Recovery group, Toxic effect, Sperm characteristics, Testicular histology, Ether anesthesia, Distilled water, Hypothalamus, Prostate gland, Serum testosterone level, Analgesic, Testosterone Level, Sperm, Testosterone, Hormonal milieu, Gynecomastia, Hyperprolactinemia, Student t-test, Conventional method, Epididymal sperm count, Hyperprolactinaemia, Reproductive impairment, High dose, Low dose, Dopamine receptor, Accessory reproductive organs, Sperm abnormalities, Gonadotrophin releasing hormone, Dose dependent increase, Antipsychotic drug, Cardiac puncture, TESTIS, Organ weight, Vascular congestion, Prolactin level, Antiemetic, Antiepileptic drug, High dose group, Haemocytometer, Pharmacokinetic, Antipsychotic medication, Haematoxylin and eosin, Spermatozoa, Epididymis, Absolute organ weight, Albino rat, Estrogen, Antifertility actions, Male Albino Rat, Seminal vesicle, Loss of Libido, Circulating Androgen Levels, Testicular function, Drug withdrawal, Antihypertensive agent, Enzyme immunoassay, Histopathological alteration, Blood vessel, FSH and LH, Serum levels of testosterone, Seminiferous tubule, Morphological defects, Gonadal response, Reproduction, Sperm function, Male reproductive function, Epididymal sperm motility, Leydig cell, Antipsychotic, Thioridazine, Antipsychotic drug treatment, Chlorpromazine, Androgen, Calming Properties, Psychiatric patient, Severe degeneration, Phenothiazine, Anaesthetic effect, Student 't' test, Formal saline, Control rat, Sperm abnormality, Seminiferous tubule degeneration, Drug-treated rats, Male reproductive efficiency, Chemical interference, Hypospermatogenesis.