Sheikh A. Saeed, Naheed Anwar, Khalid M. Khan, Noorjehan Sarfraz


Background: 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 to
inhibit ovarian prostaglandins synthesis in mammals, birds, fish and reptiles. However, the effects of its
chronic 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 by
radioimmunoassay. Moreover, we also studied the direct effect of indomethacin in vitro on luteinizing
hormone stimulated testosterone secretion from the Leydig cells isolated from various treatment
groups. Results: Indomethacin treatment for 50 days caused a significant but reversible decrease in
prostate 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 was
significantly reduced when these cells were challenged with luteinizing hormone in the presence of
indomethacin, (p<0.05). Testosterone concentration in the testicular tissue and testicular interstitial fluid
reduced after indomethacin treatment (p<0.05). Conclusion: Due to its significant inhibition of key
reproductive hormones, indomethacin effectively inhibits reproductive functions if used on a long-term
basis. In his study, we have identified potential risks in the long-term use of cyclooxygenase inhibitors.
Keywords: Cyclooxygenase inhibitor, reproductive functions, male rats

Full Text:



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.

Prostaglandins 1973;3:461–7.

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.

Prostaglandins 1990;39(1):39–51.

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.

Reproduction 2002;123:639–49.

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)

http://www.ayubmed.edu.pk/JAMC/PAST/21-3/Saeed.pdf 71

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.

Endocrinology 1986;118:32–7.

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.

Springer Heidelberg.

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

Lett 1993;330(2):156–60.

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



  • There are currently no refbacks.

Contact Number: +92-992-382571

email: [jamc] [@] [ayubmed.edu.pk]