Abubakar A. Shaikh

Effect of IUDs, Prostaglandins and Indomethacin on Decidual Cell Reaction in the Rat

Abstract The presence of an intrauterine device in the pseudopregnant (PSP) rat suppressed decidual cell reaction (DCR). Treatment with PGF 2α or PGE 2 also suppressed DCR, but had no effect on IUD horn. Treatment with PGF 2α from days 1–4 before trauma in ovariectomized rats treated with estradiol and progesterone did not have a significant effect on DCR. However, when PGF 2α was given for 4 days after trauma there was significant inhibition of DCR indicating a direct endometrial effect of PGF 2α . Inhibition of DCR was also recorded when indomethacin was administered to intact PSP or to ovariectomized rats maintained on estradiol and progesterone. This indicated that prostaglandins probably are necessary for normal DCR.

The effect of prostaglandin E2 in inducing sedation in the rat

Abstract A single subcutaneous injection of 0.5 mg of PGE 1 or PGE 2 in the rat rapidly exerted a sedative or tranquillizing effect and also induced an increased respiratory rate, flushing of the extremities and mild diarrhea. PGF 2 α, PGA 1 , or PGA 2 did not have this action, even at a dose of 5.0 mg/rat. Neither did they enhance nor reduce the effect of PGE 2 when given concurrently. Pentobarbital, at one half the normal anesthetic dose, when given in conjunction with PGE 2 , induced deep anesthesia. However, Mikedamide, epinephrine, aspirin and ethyl alcohol, did not in any way decrease the sedative action of PGE 2 . It is postulated that the major effect exerted by the E prostaglandins may result from a reduction in cerebral blood flow.

Regulation of menstrual cycle and termination of pregnancy in the monkey by estradiol and PGF2α

Abstract Four monkeys (Macaca Fascicularis) were given daily injections of 12 μg estradiol for 3 days starting on day 18 or 19 of the menstrual cycle and from day 3 of the estradiol treatment they were given daily injections of 15 mg PGF 2α . On the 3rd, 4th or 5th day of the treatment with PGF 2α all of the monkeys showed menstrual bleeding. Thus in every case there was shortening of the luteal phase of the cycle. Injections of PGF 2α alone, for 5 days, did not have this effect. In the pregnant monkey, treatment with 15 mg PGF 2α for 5 days, did not terminate pregnancy, whereas only 3 injections of the same dose of PGF 2α caused abortion in another monkey pretreated with 12 μg estradiol for 3 days. It is postulated that: 1. Administration of estrogen may cause a block of gonadotrophin release by a negative feedback mechanism. 2. Estrogen may also cause the release of endogenous prostaglandins. 3. The corpus luteum due to lack of gonadotrophins may become more vulnerable to exogenously administered and possibly also to endogenously secreted prostaglandins. 4. Estrogen may act directly on the ovary and make the luteal cells more sensitive to prostaglandins, for example by causing changes in vascular permeability.

Prostaglandins E and F in uterine venous plasma in relation to peripheral plasma levels of progesterone and 20α-hydroxyprogesterone in the rat throughout pregnancy and parturition

Prostaglandins E and F in uterine venous plasma and progesterone (P) and 20alpha-hydroxyprogesterone (20alpha-OH-P) in peripheral plasma were measured by radioimmunoassays throughout pregnancy and parturition in the rat. E Prostaglandins are low (approx. 2 ng/ml) and maintain a more or less constant level throughout most of the pregnancy except just before parturition when they rise to 3.8 ng/ml on day 20. F Prostaglandin levels are always higher than E prostaglandins and show distinct peaks around day 5 (5 ng/ml), day 11 (7 ng/ml), and before parturition (8.4 ng/ml). Progesterone levels are higher than 20alpha-OH-P levels throughout most of the pregnancy (day 6-20); however, during early pregnancy (day 1-5) and before parturition more 20alpha-OH-P than P is present in peripheral blood. The possible role of uterine venous prostaglandin levels in altering the 20alpha-OH-P/P ratio during pregnancy and parturition is discussed.

Steroids in the ovarian venous plasma and F prostaglandins in the peripheral plasma during pseudopregnancy and days 1–9 of pregnancy in the golden hamster

Abstract Estrone (E 1 ), estradiol (E 2 ), progesterone (P) and 17α-hydroxyprogesterone (17α-OHP) measurements were made in ovarian venous plasma and F prostaglandin (PGF) measurements were made in peripheral plasma of the hamsters during pseudopregnancy (PSP) and up to day 9 of pregnancy. E 2 values began to increase from day 1 of PSP onwards plateaued on day 3 and 4, dropped significantly on day 5, rose again on day 6 reaching peak levels on day 8 and 9. During pregnancy a similar trend was seen although the E 2 values in general were lower. P values in PSP hamsters started to rise from day 1 reached a peak on day 6, then declined reaching the lowest levels on day 9. In the pregnant hamsters the concentration of P reached a peak on the evening of day 4, then declined reaching the lowest levels on day 7, and increased significantly on day 8 and 9. The PGF values in PSP hamsters rose from day 1 onwards reaching a peak on the evening of day 4, when both P and E 2 values were high. By day 5 the PGF values had dropped significantly and continued to decline reaching the lowest levels on the evening of day 8. The values then increased and were high on day 9. During pregnancy, PGF values were lowest between 1900–2100 h on day 4 but by 2300-0100 they had reached a peak concentration. On day 5, the values had dropped significantly and remained unchanged until day 9. The E 1 values in PSP and pregnancy showed a pattern similar to that of E 2 . The 17α OHP values during PSP showed a peak concentration on day 1 and on day 7 and were low at other times. In pregnant hamster the 17α-OHP values showed a sharp increase on day 9. From this study it appears that the hamster ovary unlike that of the rat secretes appreciable quantities of estrogens during pregnancy and PSP. P secretion on the other hand seems to be at a very low level compared to that of the rat. This may explain why hamsters are much more susceptible to luteolytic agents compared to rats and resistant to antifertility effects of estrogens. The surge of PGF associated with increased E 2 and P concentration on day 4 is not clear. Whether it is involved in the process of implantation remains to be determined.

Uterine and peripheral plasma F-prostaglandins correlated with peripheral progesterone in cyclic rats

Abstract Radioimmunoassay (RIA) measurements of F-prostaglandins (PGF) were made in uterine venous and peripheral venous plasma. RIA determinations of progesterone (P) were also made in the peripheral venous plasma from the same rats. Concentrations of PGF in uterine venous plasma were lowest between 1000–1200 h of estrus (6.07 ng/ml), peaked at metestrus between 1000–1200 h (12.50 ng/ml), decreased on the day of diestrus between 1000–1200 h (10.25 ng/ml) and continued to decline at 1000–1200 h of proestrus (8.48 ng/ml). Thereafter there was a significant increase in the values between 1400–1600 h (10.54 ng/ml) which by 1900–2100 h had dropped again (7.17 ng/ml) and remained unchanged between 2300-0100 h. Between 0200–0400 h on the day of estrus, however, the values again showed a significant increase at the time when most of the animals ovulated. The first peak concentration of PGF in the peripheral venous plasma was also recorded between 1000–1200 h of metestrus, but was not significantly different from the values recorded on the day of diestrus and proestrus between 1000–1200 h. The second peak occurred at the same time as that recorded in uterine venous plasma. The lowest levels of progesterone were between 1000–1200 h on the day of proestrus (17.97 ng/ml). Then the values began to rise reaching a peak (46.14 ng/ml) between 1900–2100 h. Thereafter the values declined. This drop was associated with increase in both peripheral and uterine PGF.

Effects of sequential treatment with estradiol and PGF2α on the length of the primate menstrual cycle

Abstract A total of 27 monkeys (M. Fascicularis) whose control cycle lengths ranged from 28 to 32 days were used in this study. All the treatments described below started either on day 17 or 18 of the cycle. Six monkeys received daily injections of 20 μg estradiol-17β (E 2 ) for 5 consecutive days. Although a drop in blood progesterone (P) did occur due to this treatment, no shortening of the luteal phase of the cycle was recorded. Seven monkeys received daily injections of 15 mg PGF 2α (prostaglandin-F 2α ) for 4 or 5 days. These monkeys also showed a drop in blood P levels; moreover 5 of these monkeys had vaginal bleeding for 2–3 days starting either on day 19 or 20 of the cycle. This bleeding did not appear to be a normal physiological menstrual flow, since all of the monkeys commenced menstrual flow at the expected time. Four monkeys received daily injections of 10 mg P for 3 days. These monkeys also had normal cycle lengths in spite of the treatment. Finally 9 monkeys received daily injections of 20 μg E 2 for 3 days, and starting on the third day of E 2 treatment these monkeys also received injections of 15 mg PGF 2α for 4 or 5 days. Shortened cycle lengths were recorded in 8/9 monkeys in this group. Six monkeys had 22-day cycles, 2 monkeys had 24-day cycles and the remaining monkey had a cycle length of 26 days. Thus 8/9 monkeys had shortened luteal phases due to sequential treatment of E 2 and PGF 2α . The cycle lengths in all the treatment groups were normal subsequent to treatments. These results provide potentially useful information for further studies in the human as a method of contraception.

Peripheral plasma levels of E and F series prostaglandins during pseudopregnancy in the rat

Abstract The purpose of this study was to determine if changes in peripheral levels of E or F series prostaglandin (PGE or PGF) during pseudopregnancy (PSP) in the rat can be correlated with the changes in peripheral levels of total progestin (Total P), and if estrogen surge on day 4 is associated with increased levels of PGE or PGF. The results indicate that an increase in the concentration of PGF on day 7 may have precipitated a gradual decline in peripheral P. However, no correlation was detected between PGE and peripheral total P. Furthermore, no preimplantation increase in PGE or PGF levels was detected, even though the concentrations of these PGs were relatively high during the first 4 days of PSP.

Pharmacologic induction of luteolysis in cynomolgus monkeys (Macaca fascicularis)

Earlier studies reported from this laboratory demonstrated the luteolytic effect of a 5-day sequential regimen of 3 days of estrogen overlapped with 3 days of PGF2 alpha administered during the midluteal phase to cynomolgus monkeys. In this study, a different regimen, containing estrogen, lower doses of PGF2 alpha, and methylergonovine maleate (MEM), was used. Individual components of this modified sequential regimen were not effective as luteolytic agents. When 3 days of estrogen (40 micrograms of depoestradiol cypionate [DEC] on the first day and 40 micrograms of estradiol benzoate [EB] on second and third day) was followed by 3 days of MEM (400 micrograms, twice daily) overlapping 1 day of estrogen treatment, there was a significant shortening of the length of the menstrual cycle (less than 26 days) in eight of 10 animals, with a concomitant decline in plasma levels of progesterone. When a low dose of MEM (100 micrograms, twice daily), which was completely ineffective in shortening cycle lengths with the same estrogen treatment, was administered alternately with PGF2 alpha (5 mg twice daily, 11 of 14 animals had shortened cycles, with an associated decline in levels of progesterone. PGF2 alpha and MEM without the estrogen pretreatment did not have a significant effect on cycle lengths or blood levels of progesterone, thus demonstrating a synergism between estrogen and the other compounds in inducing luteolysis. Since the agents used in these sequential regimens have potent effects on the uterus, the treatments were repeated in hysterectomized monkeys to determine whether the uterus was involved in the mediation of luteolysis. These treatments caused a significant drop in plasma levels of progesterone by the tenth day after the preovulatory estrogen peak, thus demonstrating that the uterus is not essential to the luteolytic action.