EFFECT OF CHRONIC TREATMENT WITH A CYCLOOXYGENASE INHIBITOR ON REPRODUCTIVE PARAMETERS IN MALE RAT
AbstractBackground: Indomethacin is a member of non-steroidal anti-inflammatory drugs (NSAIDs)commonly used for treatment of gout, arthritis, and other inflammatory conditions. It has been shown toinhibit ovarian prostaglandins synthesis in mammals, birds, fish and reptiles. However, the effects of itschronic administration on male reproductive functions remain largely unknown. Using rat as a model,we studied the effect of chronic treatment with indomethacin on the male reproductive system.Methods: Testosterone was measured in the serum, testicular tissue, and testicular interstitial fluid byradioimmunoassay. Moreover, we also studied the direct effect of indomethacin in vitro on luteinizinghormone stimulated testosterone secretion from the Leydig cells isolated from various treatmentgroups. Results: Indomethacin treatment for 50 days caused a significant but reversible decrease inprostate weight, epididymal sperm reserves and sperm motility score compared with control rats(p<0.05). In vitro stimulation of Leydig cells isolated from treated rat’s testes with luteinizing hormone(250 µIU) produced significantly reduced testosterone compared with cells from control groups(p<0.05). Furthermore, stimulatory effect of luteinizing hormone on the control Leydig cells wassignificantly reduced when these cells were challenged with luteinizing hormone in the presence ofindomethacin, (p<0.05). Testosterone concentration in the testicular tissue and testicular interstitial fluidreduced after indomethacin treatment (p<0.05). Conclusion: Due to its significant inhibition of keyreproductive hormones, indomethacin effectively inhibits reproductive functions if used on a long-termbasis. In his study, we have identified potential risks in the long-term use of cyclooxygenase inhibitors.Keywords: Cyclooxygenase inhibitor, reproductive functions, male rats
Sagi A, Silkovsky J, Fleisher-Berkovich S, Danon A, Chayoth R.
Prostaglandin E2 in previtellogenic ovaries of the prawn
Macrobrachium rosenbergii: synthesis and effect on the level of
cAMP. Gen Comp Endocrinol 1995;100:308–13.
Priddy AR, Killick SR. Eicosanoids and ovulation.
Prostaglandins Leukot Essent Fatty Acids 1993;49:827–31.
Badr FM. Effect of sexual maturation and androgens on
prostaglandin levels in tissues of the male reproductive system in
mice. Endocrinology 1976;98(6):1523–7.
Herrero MB, Viggiano JM, Boquet M, Gimeno MA.
Prostaglandin modulation of mouse and human sperm
capacitation. Prostaglandins Leukot Essent Fatty Acids
Kelly RW, Critchley HO. Immunomodulation by human seminal
plasma: a benefit for spermatozoon and pathogen? Hum Reprod
Cosentino MJ, Takihara H, Burhop JW, Cockett AT. Regulation
of rat caput epididymidis contractility by prostaglandins. J Androl
Sato T, Jyujo T, Iesaka T, Ishikawa J, Igarashi M. Follicle
stimulating hormone and prolactin release induced by
prostaglandins in rat. Prostaglandins 1974;5:483–90.
Ojeda SR, Capdevila J, Snyder G, McCann SM, Negro-Vilar A,
Falck JR. Involvement of arachidonic acid metabolites in the
control of hypothalamic-pituitary function. Adv Prostaglandin
Thromboxane Leukot Res 1985;15:559–60.
Carlson JC, Barcikowski B, McCracken JA. Prostaglandin F2
alpha and the release of LH in sheep. J Reprod Fertil
Tsafriri A, Koch Y, Lindner HR. Ovulation rate and serum LH
levels in rats treated with indomethacin or prostaglandin E2.
Stone S, Khamashta MA, Nelson-Piercy C. Nonsteroidal antiinflammatory drugs and reversible female infertility: is there a
link? Drug Saf 2002;25:545–51.
Espey LL, Stein VI, Dumitrescu J. Survey of antiinflammatory
agents and related drugs as inhibitors of ovulation in the rabbit.
Fertil Steril 1982;38:238–47.
Shimada K, Olson DM, Etches RJ. The effect of indomethacin
on ovarian prostaglandin release in hens. Biol Reprod.
Goetz FW. Hormonal control of oocyte final maturation and
ovulation in fishes. In Hoar WS,Randall DJ,Donaldson EM
(eds): Fish Pathology IX B. New York: Academic Press; 1983.
Guillette LJ Jr, Gross TS, Matter JH, Palmer BD. Arginine
vasotocin-induced prostaglandin synthesis in vitro by the
reproductive tract of the viviparous lizard Sceloporus jarrovi.
Gaytan F, Tarradas E, Morales C, Bellido C, Sanchez-Criado JE.
Morphological evidence for uncontrolled proteolytic activity
during the ovulatory process in indomethacin-treated rats.
Elvin JA, Yan C, Matzuk MM. Growth differentiation factor-9
stimulates progesterone synthesis in granulosa cells via a
J Ayub Med Coll Abbottabad 2009;21(3)
prostaglandin E2/EP2 receptor pathway. Proc Natl Acad Sci
el-Banna AA. Treatment with prostaglandins reduces the
antifertility effect of indomethacin in rabbits. Comp Biochem
Physiol C 1986;85:21–3.
Yegnanarayan R, Joglekar GV. Anti-fertility effect of nonsteroidal anti-inflammatory drugs. Jpn J Pharmacol
Saeed SA, Zaidi AA, Pertani SA. Effect of chronic treatment
with a cyclooxygenase inhibitor (indomethacin) on the pituitarytesticular axis. Med Sci Res 1995;23:85–7.
Chan CC, Boyce S, Brideau C, Ford-Hutchinson AW, Gordon R,
Guay D, et al. Pharmacology of a selective cyclooxygenase-2
inhibitor, L-745,337: a novel nonsteroidal anti-inflammatory
agent with an ulcerogenic sparing effect in rat and nonhuman
primate stomach. J Pharmacol Exp Ther 1995;274:1531–7.
Riendeau D, Percival MD, Boyce S, Brideau C, Charleson S,
Cromlish W, et al. Biochemical and pharmacological profile of a
tetrasubstituted furanone as a highly selective COX-2 inhibitor.
Br J Pharmacol 1997;121:105–17.
Vane J. Towards a better aspirin. Nature 1994;367(6460):215–6.
Tennant JR. Evaluation of the Trypan Blue Technique for
Determination of Cell Viability. Transplantation 1964;2:685–94.
Adams ML, Cicero TJ. Effects of alcohol on beta-endorphin and
reproductive hormones in the male rat. Alcohol Clin Exp Res
Mann DR, Orr TE. Effect of restraint stress on gonadal
proopiomelanocortin peptides and the pituitary-testicular axis in
rats. Life Sci 1990;46:1601–9.
Sharpe RM. Local control of testicular function. Q J Exp Physiol
Valenca MM, Negro-Vilar A. Proopiomelanocortin-derived
peptides in testicular interstitial fluid: characterization and
changes in secretion after human chorionic gonadotropin or
luteinizing hormone-releasing hormone analog treatment.
Amann RP, Johnson L, Thompson DL, Jr., Pickett BW. Daily
spermatozoal production, epididymal spermatozoal reserves and
transit time of spermatozoa through the epididymis of the rhesus
monkey. Biol Reprod 1976;15:586–92.
Cosentino MJ, Pakyz RE, Fried J. Pyrimethamine: an approach
to the development of a male contraceptive. Proc Natl Acad Sci
Midgley AR Jr, Niswender GD, Rebar RW. Principles for the
assessment of the reliability of radioimmunoassay methods
(precision, accuracy, sensitivity, specificity). Acta-EndocrinolSuppl-(Copenh) 1969;142:163–84.
Wong PYD., Huang S, Leung AYH, Fu WO, Chung YW, Zhou
TS, et al. Physiology and pathophysiology of electrolyte transport
in the epididymis. in spermatogenesis-fertlization-contraception:
molecular, cellular and endocrine events in male reproduction.
Schering Foundation Series, ed. Nieschlag, E.,1992; p.319–44.
Tippetts MT, Varnum BC, Lim RW, Herschman HR. Tumor
promoter-inducible genes are differentially expressed in the
developing mouse. Mol Cell Biol 1988;8:4570–2.
O'Neill GP, Ford-Hutchinson AW. Expression of mRNA for
cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS
Cosentino MJ, Cockett AT. Structure and function of the
epididymis. Urol Res 1986;14(5):229–40.
Cooke BA, Dirami G, Chaudry L, Choi MS, Abayasekara DR,
Phipp L. Release of arachidonic acid and the effects of
corticosteroids on steroidogenesis in rat testis Leydig cells. J
Steroid Biochem Mol Biol 1991;40(1–3):465–71.
Moraga PF, Llanos MN, Ronco AM. Arachidonic acid release
from rat Leydig cells depends on the presence of luteinizing
hormone/human chorionic gonadotrophin receptors. J Endocrinol
Journal of Ayub Medical College, Abbottabad is an OPEN ACCESS JOURNAL which means that all content is FREELY available without charge to all users whether registered with the journal or not. The work published by J Ayub Med Coll Abbottabad is licensed and distributed under the creative commons License CC BY ND Attribution-NoDerivs. Material printed in this journal is OPEN to access, and are FREE for use in academic and research work with proper citation. J Ayub Med Coll Abbottabad accepts only original material for publication with the understanding that except for abstracts, no part of the data has been published or will be submitted for publication elsewhere before appearing in J Ayub Med Coll Abbottabad. The Editorial Board of J Ayub Med Coll Abbottabad makes every effort to ensure the accuracy and authenticity of material printed in J Ayub Med Coll Abbottabad. However, conclusions and statements expressed are views of the authors and do not reflect the opinion/policy of J Ayub Med Coll Abbottabad or the Editorial Board.
USERS are allowed to read, download, copy, distribute, print, search, or link to the full texts of the articles, or use them for any other lawful purpose, without asking prior permission from the publisher or the author. This is in accordance with the BOAI definition of open access.
AUTHORS retain the rights of free downloading/unlimited e-print of full text and sharing/disseminating the article without any restriction, by any means including twitter, scholarly collaboration networks such as ResearchGate, Academia.eu, and social media sites such as Twitter, LinkedIn, Google Scholar and any other professional or academic networking site.