Ovulation Block by Indomethacin, an Inhibitor of Prostaglandin Synthesis: A Study of Its Site of Action in Rats

Sato, Takehito; Taya, Kazuyoshi; Jyujo, Toshikuni; Igarashi, Michiko

doi:10.1530/jrf.0.0390033

Cited by 35 publications

(9 citation statements)

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“…While the first increase in FSH secretion occurs synchronized with the preovulatory luteinizing hormone (LH) surge during the mid-afternoon of proestrus, depending on gonadotropin-releasing hormone (GnRH), whereas, the secondary increase in FSH secretion occurs during the early morning of estrus without an LH surge. This secondary FSH surge is brought about by an abrupt reduction of inhibin secretion, a selective inhibitor of pituitary FSH secretion, in the granulosa cell after early luteinization by LH surge [4,7,10,11,19,27,34,44], and the prolonged increase in circulatory FSH is thought to recruit antral follicles for succeeding estrous cycle.It has been well established that indomethacin, a potent inhibitor of prostaglandin endoperoxide synthetase (PGS), blocks ovulation when it is administered during preovulatory gonadotropin surges [1,33,42]. The drug is thought to inhibit ovulation by acting directly on the ovary, where prostaglandin synthesis markedly increases in preovulatory follicles after gonadotropin surges [8,26,38].…”

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confidence: 99%

“…It has been well established that indomethacin, a potent inhibitor of prostaglandin endoperoxide synthetase (PGS), blocks ovulation when it is administered during preovulatory gonadotropin surges [1,33,42]. The drug is thought to inhibit ovulation by acting directly on the ovary, where prostaglandin synthesis markedly increases in preovulatory follicles after gonadotropin surges [8,26,38].…”

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confidence: 99%

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Effects of Indomethacin on the Selective Release of Follicle-Stimulating Hormone during the Period of Ovulation in the Rat.

Shirota

Watanabe

Taya

et al. 1998

The Journal of Veterinary Medical Science

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ABSTRACT. To determine whether indomethacin, a potent inhibitor of prostaglandins endoperoxide synthetase, affects the selective folliclestimulating hormone (FSH) surge during the period of ovulation, the compound was administered intravenously (iv), concurrent with 10 IU human chorionic gonadotropin (hCG), to diestrous female rats at 16:00 hr. Indomethacin inhibited the number of ovulations in a dosedependent manner, and treatment with 500 µg indomethacin reduced number of oocytes in the ampullae most effectively without enteric lesions. In the histological observation, oocytes that had began to mature were found not only in unruptured luteinized follicles but also in ovarian interstitium beneath ruptured luteinized follicle. Despite the inhibitory effects of indomethacin on ovulation, peri-ovulatory FSH and progesterone surges occurred in comparable levels and duration to vehicle-treated animals. These results indicate that indomethacininduced inhibition of prostaglandin synthesis does not affect the selective release of FSH during the peri-ovulatory period. [30], and that pretreatment with indomethacin reduces these effects of PGs on hypothalamicpituitary axis [32]. On the other hand, indomethacin decreased peripheral levels of inhibin during the period of eguine chorionic gonadotropin (eCG)-stimulated and -non stimulated folliclular development in immature rats [12][13][14] with an increase of peripheral FSH level [13]. However, these reports do not provide an answer to the question whether indomethacin treatment at the dose level to inhibit ovulation affects the secondary FSH surge which has been observed during the period of ovulation.The present study was undertaken to predict whether indomethacin affects the secondary FSH surge, and effects of indomethacin on the selective release of FSH during the period of induction of ovulation in diestrous rats by hCG [28] were examined by measuring plasma levels of FSH after concurrent injection of hCG and indomethacin at the dose level to inhibit inducing ovulation. Plasma levels of LH and progesterone were also determined to examine effects of the compound on hypothalamic-pituitary axis and luteinization, respectively, and histological changes in the ovary were examined for oocyte maturation and ovulation. The present results provide the evidence that indomethacin at the dose level to inhibit ovulation does not affect the selective release of FSH during the period of ovulation, suggesting that PGS-generated arachidonic acid metabolites might not be involved in the rapid fluctuation of inhibin/ activin biosynthesis during this period. Ovulation is the process by which gametes are supplied for fertilization; in addition, ovulation promotes the ensuing ovulatory cycles unless fertilization has occurred in the rat. Once preovulatory gonadotropin surges occur, mitotic maturation of the oocytes is initiated and is followed by luteinization of the granulosa cells and rupture of folliclular walls in the Graaffian follicle. A new set of follicles, which reach the antral s...

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Effects of Indomethacin on the Selective Release of Follicle-Stimulating Hormone during the Period of Ovulation in the Rat.

Shirota

Watanabe

Taya

et al. 1998

The Journal of Veterinary Medical Science

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Adult female rats of the Holtzman strain were used 5 weeks after ovariectomy.

…”

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Effects of Indomethacin, an Inhibitor of Prostaglandin Synthesis, on the Hypothalamic-Pituitary System in Rats

Sato¹,

Jyujo²,

Hirono³

et al. 1975

Journal of Endocrinology

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Several investigators (Tsafriri, Koch & Lindner, 1973;Sato, Taya, Jyujo & Igarashi, 1974) have reported that a single injection of indomethacin, an inhibitor of prostaglandin (PGs) synthesis, does not block luteinizing hormone (LH) release but exerts its anti-ovulatory action directly on the ovary. However, it has been shown (Harms, Ojeda & McCann, 1973) that PGs have stimulatory effects at various levels of the hypothalamic-pituitary system.Adult female rats of the Holtzman strain were used 5 weeks after ovariectomy. Serum or plasma, and pituitary levels of LH were determined using a radioimmuno¬ assay kit (NIAMD-NIH). In Expt 1, 3 mg indomethacin (Sumitomo Kagaku Pharmaceutical Co., Osaka) were injected s.c. in 0-2 ml 15 % gelatin, with or without PGF2ct (Ono Pharmaceutical Co., Osaka) (0-8 mg/rat) daily for 5 days and blood samples were collected 24 h after the last injection. In Expt 2, indomethacin was implanted into the median eminence (ME) of the rats. The cannulae for indomethacin implants were prepared according to the method of Corbin & Cohen (1966), by stand¬ ing 20 gauge stainless steel tubes in a melted mixture of indomethacin (50 mg) and cocoa butter (0-5 g) at 38°C. Seven days after implantation, the rats were anaes¬ thetized with ether and blood samples were collected. The anterior pituitary was homogenized in saline, extracted overnight at 4°C , centrifuged and the supernatant used for LH assay. Localization of the implants was confirmed macroscopically and microscopically. In Expt 3, 100/¿g oestradiol benzoate and 10 mg progesterone (Schering AG Berlin) were injected s.c. in 0-2 ml sesame oil on the morning of day 0. Indomethacin injections (2 mg in 0-2 ml gelatin) were then given daily to 12 rats for 3 days including day 0. Control injections of gelatin alone were given to a further 12 rats. Twenty-four hours after the last injection, 100 ng LH-releasing hormone (Daiichi Pharmaceutical Co., Tokyo) (LH-RH) were injected into the jugular vein of each animal except for six of the gelatin-control rats, which received 1 ml isotonic saline instead. Blood samples (1 ml) were obtained from the jugular vein immediately before and 10 min after the injection of LH-RH. In Expt 4, indomethacin (2 mg in 0-2 ml gelatin) was injected s.c, daily for 4 days. Twenty-four hours after the last injection, 50 µg (in 5 µ\) PGE2 (prepared by dissolving in 95 % ethanol followed by addition of 9 parts 0-02 % Na2C03 to one part solution) were injected into the third ventricle of animals anaesthetized with ether (Hedge, 1971). Injection was made with

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“…An ovum was seen in the antrum of the cyst in the animal in the metestrus phase and one of those in the estrus phase. Indomethacin is an inhibitor of prostaglandin synthesis and blocks ovulation in rats (Sato et al, 1974). Shirota et al (1998) reported that a single intravenous injection of 500 μg indomethacin with 10 IU human chorionic gonadotropin induced unruptured luteinized follicles in the ovaries of rats without causing enteric lesions.…”

Section: Discussionmentioning

confidence: 99%

“…Many non-clinical toxicity studies have clearly shown NSAID-induced gastrointestinal damage or renal papillary necrosis (Khan et al, 1998;Satoh et al, 1981). In addition, indomethacin has been thought the preovulatory follicles of rat ovaries, where prostaglandin synthesis is markedly increased (Sato et al, 1974;Tsafriri et al, 1972;Armstrong and Grinwich, 1972).…”

Section: Introductionmentioning

confidence: 99%

Collaborative work on evaluation of ovarian toxicity 12) Effects of 2- or 4-week repeated dose studies and fertility study of indomethacin in female rats

et al. 2009

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-2-week and 4-week general toxicity studies of indomethacin, a nonselective inhibitor of cyclooxygenase 1 and 2, were performed using rats. A female fertility study was also conducted to comto assess whether a precise histopathological examination, taking the morphological changes the female reproductive organs undergo during each estrus phases into account, can evaluate toxicity to the ovaries, and to determine the optimal administration period for detecting ovarian toxicity. Indomethacin was administered on a daily basis to female Sprague-Dawley rats at doses of 0, 0.4, 1.3, or 4 mg/kg in the both the general toxicity studies and the female fertility study. In the general toxicity studies, unruptured follicles or luteinized cysts were observed histopathologically in the 4 mg/kg group in both the 2-week and 4-week studies. In addition, follicular cysts were found in the 4 mg/kg group in the 4-week study. Estrous cyclicity was not disturbed in both studies. There were no histopathological changes in the ovaries of the 1.3 mg/kg group in general toxicity studies. In the female fertility study, no toxic effects on female fertility parameters were detected in the 0.4 and 1.3 mg/kg group treated with indomethacin, but 8 of 10 rats in -in the ovary. In addition, 4 weeks of dosing maybe required for induction of follicular cysts, although we could not clearly show that these histopathological changes would affect female fertility functions. These present studies suggest that a precise histopathological examination may be able to predict the effect of test articles on female reproductive functions.

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Ovulation Block by Indomethacin, an Inhibitor of Prostaglandin Synthesis: A Study of Its Site of Action in Rats

Cited by 35 publications

References 6 publications

Effects of Indomethacin on the Selective Release of Follicle-Stimulating Hormone during the Period of Ovulation in the Rat.

Effects of Indomethacin on the Selective Release of Follicle-Stimulating Hormone during the Period of Ovulation in the Rat.

Effects of Indomethacin, an Inhibitor of Prostaglandin Synthesis, on the Hypothalamic-Pituitary System in Rats

Collaborative work on evaluation of ovarian toxicity 12) Effects of 2- or 4-week repeated dose studies and fertility study of indomethacin in female rats

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