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Optimum time for administration of indomethacin to inhibit ovulation in the rabbit
PROSTAGLANDINS
OPTIMUM TIME FOR ADMINISTRATION OF INDOMETHACIN TO INHIBIT OVULATION IN THE RABBIT Lawrence L. Espeyl Department of Biology Trinity University San Antonio, Texas 78284 ABSTRACT The antiinflammatory agent, indomethacin, inhibits ovulation in mammals by interfering with the synthesis of prostaglandins in preovulatory follicles. To determine the optimum time to administer this inhibitor, indomethacin was given at specific intervals from 10 h before, and up to 9 h after, the ovulatory process had been initiated by hCG (50 I.U./kg). The drug dosage ranged from 1.25 mg/kg to 40 mg/kg. The optimum time to give indomethacin was at 7-8 h after hCG (i.e., 2-3 h before expected rupture of the follicle) at which time the minimum effective dose was 2.5 mg/kg. Since a significant elevation in prostaglandin synthesis occurs as early as 3-5 h after hCG stimulation of rabbit follicles (l), these results reveal that nonsteroidal antiinflammatoryagents can interrupt the ovulatory process even after the follicle has begun producing substantial amounts of prwlandins. The data suggest that prostaglandins need to be produced continuously in the follicle up to the time of actual rupture, or else that indomethacin is interfering with some other aspect of the ovulatory process which transpires after the elevation of prostaglandins.
lCowles Professor of Life Science at Trinity University
MARCH
1982 VOL. 23 NO. 3
329
PROSTAGLANDINS
INTRODUCTION A decade ago it was discovered that indomethacin inhibits mammalian ovulation by direct action on the ovary (2). Since this discovery there have been numerous studies on the effects of indomethacin on ovulation and luteinization of mature ovarian follicles in a variety of species (3-5). The general concensus is that indomethacin acts by interfering with the production of prostaglandins in ovulatory follicles. None of the previous work has accurately determined the optimum time to administer indomethacin to inhibit ovulation, In most of the studies on rabbits (6-9), the investigators administered indomethacin at approximately the same time as LH, hCG, or coitus simply because this was the time it was given in the original work. Hovever, several reports (10-11) suggest that indomethacin may be more effective in rabbits when given 6-8 h after gonadotropin. Similarly, in rats (the other species most commonly used to study the antiovulatory action of indomethacin) the optimum time to administer indomethacin has not been established. In most studies on rats indomethacin was routinely given near the time of the LH surge, or hCG injection (12-17). Only two of these studies tested indomethacin at some time after gonadotropin stimulation (16-17). These latter reports showed that indomethacin does not inhibit ovulation in rats when given 8-10 h after gonadotropin. However, there is a contradictory report which states that indomethacin can exert an inhibitory effect in rats as late as 8 h after hCG (18r The present study was conducted to clarify the optimum time to inhibit ovulation with indomethacin. The results show that the optimum time is during the later stages of the ovulatory processeven later than the time while follicles are known to be producing elevated levels of prostaglandins. METHODS Rabbits (New Zealand White) were selected as the experimental animals because they conveniently ovulate at 10 h after receiving hCG. Indomethacin was given i.v. in doses ranging from 1.25 mg/kg to 40 mg/kg at designated intervals both before and after the ovulatory process was initiated by hCG (50 I.U./kg). Laparotomies were performed on the experimental animals at 20-24 h after they had received hCG, i.e., lo-14 h after the normal time of ovulation. The ovaries were excised and examined under a dissecting microscope to determine the number of ruptured follicles. In a random sampling of 100 rabbits there was an average of 8.88 large follicles (1.0-1.5 mm diam) per pair of ovaries. In a group of ten control animals, only 73% f 5.5% of the large follicles ruptured in response to hCG. Thus, ovulation is not an "all-ornone" phenomenon. Nor is the inhibition of ovulation absolute. Although a given dose of indomethacin may inhibit ovulation of most
330
MARCH
1982VOL.23 NO.3
PROSTAGLANDINS
of the large follicles on a pair of ovaries, one or two of the follicles sometimes still rupture. There are no established criteria to designate when such "partial" inhibition is strong, or when it is weak. For the purposes of this report, a given dose of indomethacin was considered to be strongly inhibitory if an average of no more than 30% of the large follicles ovulated in a group of three or more animals which received the same dose of indomethacin. RESULTS The earliest injection of indomethacin was at 10 h before the administration of hCG. At this time, a dose of 40 mg/kg did not inhibit ovulation (Table 1). At later test intervals the minimum doses of indomethacin that were required to strongly inhibit ovulation were: 40 mg/kg at 5 h before hCG; 30 mg/kg at 1 h before hCG; 20 mg/kg at the same time as hCG; 10 mg/kg at 1 h after hCG; 10 mg/ kg at 3 h after hCG; 5 mg/kg at 5 h after hCG; 2.5 mg/kg at 7 h after hCG; 2.5 mg/kg at 8 h after hCG; and 40 mg/kg at 9 h after hCG. Indomethacin was not given later than 9 h after hCG because the majority of rabbits ovulate within 10 h after hCG administration. TABLE 1. Average % Ovulations per Animal at Different Doses and Times of Indomethacin Administration.
a numbers in parentheses indicate animals per test group.
MARCH
1982 VOL. 23 NO. 3
331
PROSTAGLANDINS
A plot of the minimum effective dose of indomethacin required to strongly inhibit ovulation at each of the test intervals shows that the optimum time to administer indomethacin is 7-8 h after the injection of hCG, i.e., 2-3 h before the expected time of ovulation (Fig. 1). FIG. 1.
Minimum Effective Dose of Indomethacin.
0 -7
-5
-3
-1
0 +1
t3
t5
+7
OVULATION
HOURS BEFORE AND AFTER hCG INJECTION DISCUSSION The results show that the optimum time to administer indomethacin to inhibit ovulation in the rabbit is 7-8 h after gonadotropic stimulation of the ovulatory process. Furthermore, relatively high doses of indomethacin can inhibit ovulation (at least partially) as late as 9 h after gonadotropic stimulation of the follicles. This means that indomethacin can inhibit ovulation up to 1 h before the expected time of rupture, since most rabbit follicles that are mature ovulate at approximately 10 h after gonadotropic stimulation. It has been reported that prostaglandin production begins to increase significantly in rabbit follicles within 5 h after they have been stimulated by gonadotropin (1, 17, 19). By 9 h after gonadotropin PGF increases more than 60 fold, and PGE more than 15 fold. Therefore, if prostaglandins are, indeed, essential for ovulation, and if indomethacin inhibits ovulation by inhibiting prostaglandin synthesis, then the results of this report reveal two interesting points: (i) indomethacin can interrupt prostaglandin synthesis after its production has already increased in ovulatory
332
MARCH
1982 VOL. 23 NO. 3
PROSTAGLANDINS
follicles, and (ii) prostaglandins must be synthesized continuously in increasing amounts throughout the ovulatory process in order for the follicle to rupture, Verification of the above points will require the demonstration that follicle prostaglandin levels decline significantly within l-2 h after the injection of indomethacin at the optimum time of 7-8 h after gonadotropin. Otherwise, if prostaglandins do not decline, then the results would suggest that indomethacin inhibits ovulation by some mechanism other than interruption of prostaglandin synthesis. Alternative mechanisms might involve the known ability of indomethacin to inhibit the proliferation of fibroblasts (20), or its ability to interfere with proteolytic degradation of connective tissue (21-22). Still, these actions of indomethacin could be an indirect consequence of the inhibition of prostaglandin synthesis by this nonsteroidal antiinflammatory agent. Further clarification of the mechanism of action of indomethacin in ovulation will require the assay of prostaglandins in follicles that have been exposed to indomethacin after prostaglandin production has already increased during the ovulatory process. ACKNOWLEDGMENTS I appreciate the dependable technical assistance of Miss Valerie Stein and Mr. Mark Wehner. This study was supported by NIH Grant HD-14539 and by Trinity University Grant TU-111-81. The facilities at Trinity University were generously donated by the late Dr. Andrew G. Cowles. REFERENCES 1.
LeMaire, W. J., N. S . T. Yang, H. H. Behrman , and J. M. Marsh. Preovulatory Changes in the Concentration of Prostaglandins in Rabbit Graafian Foll icles. Prostaglandins 2 ; 307-376, 1973.
2.
Behrman, H. R., G. P. Orczyk and R. 0. Greep. Effect of Synthetic Gonadotrophin-Releasing Hormone (Gn-RH) on Ovulation Blockade by Aspirin and Indomethacin. Prostaglandins 1: 245258, 1972.
3.
Wallach, E. E., R. Bronson, Y. Hamada, K. H. Wright, and V. C. Stevens. Effectiveness of Prostaglandin F2a in Restoration of HMG-HCG Induced Ovulation in Indomethacin-Treated Rhesus Monkeys. Prostaglandins -10: 129-138, 1975.
4.
Lindner, H. R., U. Zor, F. Kohen, S. Bauminger, A. Amsterdam, M. Lahav, and Y. Salomon. Significance of Prostaglandins in the Regulation of Cyclic Events in the Ovary and Uterus. Adv. Prostaglandin Thromboxane Res. 8: 1371-1390, 1980.
MARCH
1982 VOL. 23 NO. 3
333
PROSTAGLANDINS
5.
Armstrong, C. T. Prostaglandins and Follicular Functions. Reprod. Fertil. -02: 283-291, 1981.
6.
Grinwich, D. L., T. G. Kennedy and D. T. Armstrong. Dissociation of Ovulatory and Steroidogenic Actions of Luteinizing Hormone in Rabbits with Indomethacin, an Inhibitor of Prostaglandin Biosynthesis. Prostaglandins 1: 89-96, 1972.
7.
Yang, N. S. T., J. M. Marsh and k'. J. LeMaire. Prostaglandin Changes Induced by Ovulatory Stimuli in Rabbit Graafian Follicles. The Effect of Indomethacin. Frostaglandins C: 395404, 1973.
8.
LeMaire, h'. J. and J. M. Marsh. Interrelationships Between Prostaglandins, Cyclic AMP and Steroids in Ovulation. J. Reprod. Fertil., (Suppl.) 2: 53-74, 1975.
9.
Phi, L. T., Y. S. Moon, and D. T. Armstrong. Effects of Systemic and Intrafollicular Injections of LH, Prostaglandins, and Indomethacin on the Luteinization of Rabbit Graafian Follicles. Prostaglandins -13: 543-552, 1977.
1G.
@'Grady, J. P., B. V. Caldwell, F. J. Auletta, and L. Speroff. The Effects of an Inhibitor of Prostaglandin Synthesis (Indomethacin) cn Ovulation, Pregnancy, and Pseudopregnancy in the Rabbit. Prostaglandins 1: 97-106, 1972.
11.
Inhibition of Ovulation and Lau, I. F., and S. K. Sadsena. Fertilization by Indomethacin and Effect of Prostaglandin-F2a cn Early Pregnancy in the Rabbit. Prostaglandins Med. 2: 425-432, 1979.
12.
Armstrong, D. T. and D. L. Grinwich. Blockade of Spontaneous and LH-Induced Ovulation in Rats by Indomethacin, an Inhibitor Frostaglandins 1: 21-28, 1972. of Prostaglandin Biosynthesis.
13.
Armstrong, 0. T. and J. Zamecnik. Pre-Ovulatory Elevation of Rat Ovarian Prostaglandins F, and its Blockade by Indomethacin. Mol. Cell. Endocrinol. 2: 125-131, 1975.
14.
Orczyk, G. P. and H. R. Behrman. Ovulation Blockade by Aspirin or Indonethacin - In -Vivo Evidence for a Role of Prostaglandin in Gonadotrophin Secretion. Prostaglandins 1: 3-13, 1972.
15.
Tsafriri, A., t!. R. Lindner, U. Zor and S. A. Lamprecht. Physiological Role of Prostaglandins in the Induction of Ovulation, Prostaglandins 2: l-10, 1972.
334
MARCH
J.
1982 VOL. 23 NO. 3
PROSTAGLANDINS
16.
Tsafriri, A., Y. Koch and H. R. Lindner. Ovulation Rate and Serum LH Levels in Rats Treated With Indomethacin or Prostaglandins 3: 461-467, 1973.
17.
Mori, T., H. Kohda, Y. Kinoshita, Y. Ezaki, N. Morimoto and Inhibition by Indomethacin of Ovulation Induced T. Nishimura. by Human Chorionic Gonadotrophin in Immature Rats Primed With J. Endocrinol. -84: 333Pregnant Mare Serum Gonadotrophin. 341, 1980.
18.
Parr, E. L. Rupture of Ovarian Fol licles at Ovulation. Reprod. Fertil., (Suppl.) 22: l-22, 1975.
19.
Yang, N. S. T., J. M. Marsh and W. J. LeMaire. Post Ovulatory Changes in the Concentration of Prostaglandins in Rabbit Graafian Follicles. Prostaglandins 5: 37-44, 1974.
20.
Hial, V., M. C. F. De Mello, Z. Horakova and M. A. Beaven. Antiproliferative Activity of Antiinflammatory Drugs in Two Mammalian Cell Culture Lines. J. Pharmacol. Exp. Ther. 202: 446-454, 1977.
21.
Pettigrew, D. W., G. H. Ho, J. Sodek, D. M. Brunette and H.-M. Wang. Effect of Oxygen Tension and Indomethacin on Production of Collagenase and Neutral Proteinase Enzymes and Their Latent Forms by Porcine Gingival Explants in Culture. Arch. Oral Biol. -23: 767-777, 1978.
22.
Comper, W. D., M. De Witt and D. A. Lowther. Effects of AntiInflammatory Drugs on Proteoglycan Degradation as Studied in Rabbit Articular Cartilage in Organ Culture. Biochem. Pharmacol. -30: 459-468, 1981.
J.
Editor: Harold R. Behrman Received: 10-26-81 Accepted: 2-2-82
MARCH
1982VOL.23NO.3
335
OPTIMUM TIME FOR ADMINISTRATION OF INDOMETHACIN TO INHIBIT OVULATION IN THE RABBIT Lawrence L. Espeyl Department of Biology Trinity University San Antonio, Texas 78284 ABSTRACT The antiinflammatory agent, indomethacin, inhibits ovulation in mammals by interfering with the synthesis of prostaglandins in preovulatory follicles. To determine the optimum time to administer this inhibitor, indomethacin was given at specific intervals from 10 h before, and up to 9 h after, the ovulatory process had been initiated by hCG (50 I.U./kg). The drug dosage ranged from 1.25 mg/kg to 40 mg/kg. The optimum time to give indomethacin was at 7-8 h after hCG (i.e., 2-3 h before expected rupture of the follicle) at which time the minimum effective dose was 2.5 mg/kg. Since a significant elevation in prostaglandin synthesis occurs as early as 3-5 h after hCG stimulation of rabbit follicles (l), these results reveal that nonsteroidal antiinflammatoryagents can interrupt the ovulatory process even after the follicle has begun producing substantial amounts of prwlandins. The data suggest that prostaglandins need to be produced continuously in the follicle up to the time of actual rupture, or else that indomethacin is interfering with some other aspect of the ovulatory process which transpires after the elevation of prostaglandins.
lCowles Professor of Life Science at Trinity University
MARCH
1982 VOL. 23 NO. 3
329
PROSTAGLANDINS
INTRODUCTION A decade ago it was discovered that indomethacin inhibits mammalian ovulation by direct action on the ovary (2). Since this discovery there have been numerous studies on the effects of indomethacin on ovulation and luteinization of mature ovarian follicles in a variety of species (3-5). The general concensus is that indomethacin acts by interfering with the production of prostaglandins in ovulatory follicles. None of the previous work has accurately determined the optimum time to administer indomethacin to inhibit ovulation, In most of the studies on rabbits (6-9), the investigators administered indomethacin at approximately the same time as LH, hCG, or coitus simply because this was the time it was given in the original work. Hovever, several reports (10-11) suggest that indomethacin may be more effective in rabbits when given 6-8 h after gonadotropin. Similarly, in rats (the other species most commonly used to study the antiovulatory action of indomethacin) the optimum time to administer indomethacin has not been established. In most studies on rats indomethacin was routinely given near the time of the LH surge, or hCG injection (12-17). Only two of these studies tested indomethacin at some time after gonadotropin stimulation (16-17). These latter reports showed that indomethacin does not inhibit ovulation in rats when given 8-10 h after gonadotropin. However, there is a contradictory report which states that indomethacin can exert an inhibitory effect in rats as late as 8 h after hCG (18r The present study was conducted to clarify the optimum time to inhibit ovulation with indomethacin. The results show that the optimum time is during the later stages of the ovulatory processeven later than the time while follicles are known to be producing elevated levels of prostaglandins. METHODS Rabbits (New Zealand White) were selected as the experimental animals because they conveniently ovulate at 10 h after receiving hCG. Indomethacin was given i.v. in doses ranging from 1.25 mg/kg to 40 mg/kg at designated intervals both before and after the ovulatory process was initiated by hCG (50 I.U./kg). Laparotomies were performed on the experimental animals at 20-24 h after they had received hCG, i.e., lo-14 h after the normal time of ovulation. The ovaries were excised and examined under a dissecting microscope to determine the number of ruptured follicles. In a random sampling of 100 rabbits there was an average of 8.88 large follicles (1.0-1.5 mm diam) per pair of ovaries. In a group of ten control animals, only 73% f 5.5% of the large follicles ruptured in response to hCG. Thus, ovulation is not an "all-ornone" phenomenon. Nor is the inhibition of ovulation absolute. Although a given dose of indomethacin may inhibit ovulation of most
330
MARCH
1982VOL.23 NO.3
PROSTAGLANDINS
of the large follicles on a pair of ovaries, one or two of the follicles sometimes still rupture. There are no established criteria to designate when such "partial" inhibition is strong, or when it is weak. For the purposes of this report, a given dose of indomethacin was considered to be strongly inhibitory if an average of no more than 30% of the large follicles ovulated in a group of three or more animals which received the same dose of indomethacin. RESULTS The earliest injection of indomethacin was at 10 h before the administration of hCG. At this time, a dose of 40 mg/kg did not inhibit ovulation (Table 1). At later test intervals the minimum doses of indomethacin that were required to strongly inhibit ovulation were: 40 mg/kg at 5 h before hCG; 30 mg/kg at 1 h before hCG; 20 mg/kg at the same time as hCG; 10 mg/kg at 1 h after hCG; 10 mg/ kg at 3 h after hCG; 5 mg/kg at 5 h after hCG; 2.5 mg/kg at 7 h after hCG; 2.5 mg/kg at 8 h after hCG; and 40 mg/kg at 9 h after hCG. Indomethacin was not given later than 9 h after hCG because the majority of rabbits ovulate within 10 h after hCG administration. TABLE 1. Average % Ovulations per Animal at Different Doses and Times of Indomethacin Administration.
a numbers in parentheses indicate animals per test group.
MARCH
1982 VOL. 23 NO. 3
331
PROSTAGLANDINS
A plot of the minimum effective dose of indomethacin required to strongly inhibit ovulation at each of the test intervals shows that the optimum time to administer indomethacin is 7-8 h after the injection of hCG, i.e., 2-3 h before the expected time of ovulation (Fig. 1). FIG. 1.
Minimum Effective Dose of Indomethacin.
0 -7
-5
-3
-1
0 +1
t3
t5
+7
OVULATION
HOURS BEFORE AND AFTER hCG INJECTION DISCUSSION The results show that the optimum time to administer indomethacin to inhibit ovulation in the rabbit is 7-8 h after gonadotropic stimulation of the ovulatory process. Furthermore, relatively high doses of indomethacin can inhibit ovulation (at least partially) as late as 9 h after gonadotropic stimulation of the follicles. This means that indomethacin can inhibit ovulation up to 1 h before the expected time of rupture, since most rabbit follicles that are mature ovulate at approximately 10 h after gonadotropic stimulation. It has been reported that prostaglandin production begins to increase significantly in rabbit follicles within 5 h after they have been stimulated by gonadotropin (1, 17, 19). By 9 h after gonadotropin PGF increases more than 60 fold, and PGE more than 15 fold. Therefore, if prostaglandins are, indeed, essential for ovulation, and if indomethacin inhibits ovulation by inhibiting prostaglandin synthesis, then the results of this report reveal two interesting points: (i) indomethacin can interrupt prostaglandin synthesis after its production has already increased in ovulatory
332
MARCH
1982 VOL. 23 NO. 3
PROSTAGLANDINS
follicles, and (ii) prostaglandins must be synthesized continuously in increasing amounts throughout the ovulatory process in order for the follicle to rupture, Verification of the above points will require the demonstration that follicle prostaglandin levels decline significantly within l-2 h after the injection of indomethacin at the optimum time of 7-8 h after gonadotropin. Otherwise, if prostaglandins do not decline, then the results would suggest that indomethacin inhibits ovulation by some mechanism other than interruption of prostaglandin synthesis. Alternative mechanisms might involve the known ability of indomethacin to inhibit the proliferation of fibroblasts (20), or its ability to interfere with proteolytic degradation of connective tissue (21-22). Still, these actions of indomethacin could be an indirect consequence of the inhibition of prostaglandin synthesis by this nonsteroidal antiinflammatory agent. Further clarification of the mechanism of action of indomethacin in ovulation will require the assay of prostaglandins in follicles that have been exposed to indomethacin after prostaglandin production has already increased during the ovulatory process. ACKNOWLEDGMENTS I appreciate the dependable technical assistance of Miss Valerie Stein and Mr. Mark Wehner. This study was supported by NIH Grant HD-14539 and by Trinity University Grant TU-111-81. The facilities at Trinity University were generously donated by the late Dr. Andrew G. Cowles. REFERENCES 1.
LeMaire, W. J., N. S . T. Yang, H. H. Behrman , and J. M. Marsh. Preovulatory Changes in the Concentration of Prostaglandins in Rabbit Graafian Foll icles. Prostaglandins 2 ; 307-376, 1973.
2.
Behrman, H. R., G. P. Orczyk and R. 0. Greep. Effect of Synthetic Gonadotrophin-Releasing Hormone (Gn-RH) on Ovulation Blockade by Aspirin and Indomethacin. Prostaglandins 1: 245258, 1972.
3.
Wallach, E. E., R. Bronson, Y. Hamada, K. H. Wright, and V. C. Stevens. Effectiveness of Prostaglandin F2a in Restoration of HMG-HCG Induced Ovulation in Indomethacin-Treated Rhesus Monkeys. Prostaglandins -10: 129-138, 1975.
4.
Lindner, H. R., U. Zor, F. Kohen, S. Bauminger, A. Amsterdam, M. Lahav, and Y. Salomon. Significance of Prostaglandins in the Regulation of Cyclic Events in the Ovary and Uterus. Adv. Prostaglandin Thromboxane Res. 8: 1371-1390, 1980.
MARCH
1982 VOL. 23 NO. 3
333
PROSTAGLANDINS
5.
Armstrong, C. T. Prostaglandins and Follicular Functions. Reprod. Fertil. -02: 283-291, 1981.
6.
Grinwich, D. L., T. G. Kennedy and D. T. Armstrong. Dissociation of Ovulatory and Steroidogenic Actions of Luteinizing Hormone in Rabbits with Indomethacin, an Inhibitor of Prostaglandin Biosynthesis. Prostaglandins 1: 89-96, 1972.
7.
Yang, N. S. T., J. M. Marsh and k'. J. LeMaire. Prostaglandin Changes Induced by Ovulatory Stimuli in Rabbit Graafian Follicles. The Effect of Indomethacin. Frostaglandins C: 395404, 1973.
8.
LeMaire, h'. J. and J. M. Marsh. Interrelationships Between Prostaglandins, Cyclic AMP and Steroids in Ovulation. J. Reprod. Fertil., (Suppl.) 2: 53-74, 1975.
9.
Phi, L. T., Y. S. Moon, and D. T. Armstrong. Effects of Systemic and Intrafollicular Injections of LH, Prostaglandins, and Indomethacin on the Luteinization of Rabbit Graafian Follicles. Prostaglandins -13: 543-552, 1977.
1G.
@'Grady, J. P., B. V. Caldwell, F. J. Auletta, and L. Speroff. The Effects of an Inhibitor of Prostaglandin Synthesis (Indomethacin) cn Ovulation, Pregnancy, and Pseudopregnancy in the Rabbit. Prostaglandins 1: 97-106, 1972.
11.
Inhibition of Ovulation and Lau, I. F., and S. K. Sadsena. Fertilization by Indomethacin and Effect of Prostaglandin-F2a cn Early Pregnancy in the Rabbit. Prostaglandins Med. 2: 425-432, 1979.
12.
Armstrong, D. T. and D. L. Grinwich. Blockade of Spontaneous and LH-Induced Ovulation in Rats by Indomethacin, an Inhibitor Frostaglandins 1: 21-28, 1972. of Prostaglandin Biosynthesis.
13.
Armstrong, 0. T. and J. Zamecnik. Pre-Ovulatory Elevation of Rat Ovarian Prostaglandins F, and its Blockade by Indomethacin. Mol. Cell. Endocrinol. 2: 125-131, 1975.
14.
Orczyk, G. P. and H. R. Behrman. Ovulation Blockade by Aspirin or Indonethacin - In -Vivo Evidence for a Role of Prostaglandin in Gonadotrophin Secretion. Prostaglandins 1: 3-13, 1972.
15.
Tsafriri, A., t!. R. Lindner, U. Zor and S. A. Lamprecht. Physiological Role of Prostaglandins in the Induction of Ovulation, Prostaglandins 2: l-10, 1972.
334
MARCH
J.
1982 VOL. 23 NO. 3
PROSTAGLANDINS
16.
Tsafriri, A., Y. Koch and H. R. Lindner. Ovulation Rate and Serum LH Levels in Rats Treated With Indomethacin or Prostaglandins 3: 461-467, 1973.
17.
Mori, T., H. Kohda, Y. Kinoshita, Y. Ezaki, N. Morimoto and Inhibition by Indomethacin of Ovulation Induced T. Nishimura. by Human Chorionic Gonadotrophin in Immature Rats Primed With J. Endocrinol. -84: 333Pregnant Mare Serum Gonadotrophin. 341, 1980.
18.
Parr, E. L. Rupture of Ovarian Fol licles at Ovulation. Reprod. Fertil., (Suppl.) 22: l-22, 1975.
19.
Yang, N. S. T., J. M. Marsh and W. J. LeMaire. Post Ovulatory Changes in the Concentration of Prostaglandins in Rabbit Graafian Follicles. Prostaglandins 5: 37-44, 1974.
20.
Hial, V., M. C. F. De Mello, Z. Horakova and M. A. Beaven. Antiproliferative Activity of Antiinflammatory Drugs in Two Mammalian Cell Culture Lines. J. Pharmacol. Exp. Ther. 202: 446-454, 1977.
21.
Pettigrew, D. W., G. H. Ho, J. Sodek, D. M. Brunette and H.-M. Wang. Effect of Oxygen Tension and Indomethacin on Production of Collagenase and Neutral Proteinase Enzymes and Their Latent Forms by Porcine Gingival Explants in Culture. Arch. Oral Biol. -23: 767-777, 1978.
22.
Comper, W. D., M. De Witt and D. A. Lowther. Effects of AntiInflammatory Drugs on Proteoglycan Degradation as Studied in Rabbit Articular Cartilage in Organ Culture. Biochem. Pharmacol. -30: 459-468, 1981.
J.
Editor: Harold R. Behrman Received: 10-26-81 Accepted: 2-2-82
MARCH
1982VOL.23NO.3
335