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  • Author: K. E. KENDLE x
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K. E. KENDLE

Summary.

Intravaginal administration of 5HT was effective in terminating pregnancy when given after implantation in the rat, provided that the tampon was allowed to remain in the vagina for 4 hr or more. Complete antifertility efficacy was associated with a prevention or reversal of the increase in ovarian weight, which occurs in untreated rats between Days 12 and 17 of pregnancy, and correlates with enlargement of the CL. Data from hysterectomized, ovariectomized and progesterone-implanted rats indicated that the effect on CL was not a cause of the antifertility effect. Intravaginal administration of 5HT was found to lead to general systemic effects.

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K. E. Kendle

Summary. The antifertility effect of RMI 12,936 in the rat is shown to be reversible. Luteal hypertrophy followed administration to pregnant, but not to pregnant hysterectomized rats. Similar hypertrophy followed administration to pseudopregnant, immature gonadotrophin-treated, and immature hysterectomized and gonadotrophin-treated rats, but the ovarian sensitivity to gonadotrophins was reduced or unchanged, suggesting that the ovarian hypertrophy is due to a direct ovarian action of RMI 12,936. Progesterone production on Day 15 of pregnancy by the enlarged ovaries following RMI 12,936 administration on Day 8 was not significantly different from control levels, but there was a highly significant reduction on Day 9.

An isomer of RMI 12,936, Isomer 201, presumed to be 7α-methyltestosterone, was shown to have antifertility and uterotrophic activities in rats similar to those of RMI 12,936. Unlike RMI 12,936, however, Isomer 201 did show significant cross-reaction in the competitive protein-binding assay for progesterone and did not cause significant reduction in peripheral progesterone levels on Day 9 after administration on Day 8.

From this and previous evidence it is concluded that RMI 12,936 inhibits progesterone synthesis, possibly by acting as an alternative substrate for ovarian Δ53-ketosteroid isomerase, and that the product is probably a competitive antagonist of progesterone at the receptor level.

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K. E. Kendle

Summary. The antifertility activities of RMI 12,936 and 7α-methyltestosterone may be reversed by progesterone implants in ovariectomized, but not in intact, rats on Day 8 of pregnancy. The presence of the ovary for 48 h after administration of RMI 12,936 is necessary for irreversible antifertility activity to be developed, and it is concluded that this activity is due to a metabolite other than 7α-methyltestosterone. 7α-Methylandrostenedione was significantly less potent than RMI 12,936 in antifertility tests, while the uterotrophic activity of RMI 12,936 was not inhibited by aromatization inhibitors, suggesting that the active metabolite is not produced by dehydrogenation or aromatization of 7α-methyltestosterone.

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K. E. KENDLE

Summary.

A new synthetic steroid, RMI 12,936, was examined for its contraceptive potential in rats and comparisons with ethinyloestradiol were also made. Marked differences in the biological effects of the compounds were found, RMI 12,936 having high antiprogestational but negligible oestrogenic activity. Administration of RMI 12,936 on Day 1 of pregnancy caused acceleration of egg transport, the initial changes being apparent within 12 hr of dosing. Termination of pregnancy was associated with a significant reduction in ovarian weight. On Day 8 of pregnancy, RMI 12,936 resulted in significant ovarian hypertrophy, apparent within 48 hr, possibly due to a luteotrophic stimulus of placental origin. Pregnancy could not be maintained by progesterone implants, indicating that utilization was inhibited. Egg transfer experiments indicated that the primary effects were probably on the maternal reproductive tract. Pregnancy was terminated after administration of RMI 12,936 on Day 19.

The compound also had antifertility activity following intravaginal administration.

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W. Arkaravichien and K. E. Kendle

Summary. Pregnant rats were injected with mifepristone (RU 486) on Day 15 of pregnancy. The force and frequency of uterine contractions, recorded by a microballoon technique, were significantly greater at 12, 24 and 36 h in treated than in control rats (11·9 ± 1·9 vs. 8·9 ± 1·2 units, 17·7 ± 3·0 vs. 10·5 ± 2·3 units and 16·8 ± 2·9 vs. 8·8 ± 1·8 units for force and 51·3 ± 9·1 vs. 29·4 ± 3·8/h, 35·4 ± 6·4 vs. 22·1 ± 4·9/h and 35·6 ± 3·2 vs. 24·6 ± 4·6/h for frequency, respectively). There was no significant difference in concentrations of prostaglandin (PG) E-2 or PGF-2α between treated and control rats at 12 h and 24 h after injection. At 36 h, 7 of 12 rats were aborting and uterine PG concentrations in these were significantly greater than in the others (1·5 ± 0·2 vs. 0·9 ± 0·2 ng PGE-2/g and 38·6 ± 19·2 vs. 16·9 ± 5·4 ng PGF-2α/g), but there was no significant difference between control and treated rats that were not aborting. Concentrations of PGE-2 and PGF-2α were significantly higher at 48 h when abortion had occurred in all animals (6·5 ± 2·6 vs. 2·4 ± 1·7 ng PGE-2/g and 30·4 ± 8·9 vs. 9·3 ± 5·6 ng PGF-2α/g). Thus, the increase in uterine contractile activity induced by mifepristone preceded significant changes in concentrations of PGE-2 and PGF-2α in the uterus and so could not have been caused by these changes.

Keywords: uterine contractions; prostaglandins; mifepristone; rat

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K. E. Kendle and Bernadette Lee

Summary. The rate of embryo transport through the mouse oviduct was unaltered by ovariectomy after ovulation, essentially unaltered by administration of progesterone after ovulation but increased by preovulatory administration of progesterone. The antiprogestational steroid RMI 12,936 caused an arrest of embryo movement when given on Day 1, 2 or 3 of pregnancy and similar, though less marked, delay was caused by R2323, another progesterone antagonist. The effects of RMI 12,936 given on Day 1 were reversed by progesterone administration after a latent period of 24–48 h. These results indicate that the egg transport process in the mouse is triggered by progesterone and requires continued progesterone activity for its maintenance.

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W. Arkaravichien and K. E. Kendle

Summary. The hypothesis that sustained uterine contractile activity is the direct cause of fetal death after progesterone withdrawal in late pregnancy in rats was investigated. Pregnant rats were subjected to progesterone withdrawal on day 15 of pregnancy by injecting 2 mg mifepristone (RU 486) kg−1 or by ovariectomy with oestradiol replacement (200 ng day−1). Uterine contractile activity (force and frequency) at 4 h, but not at 2 h, in rats injected with mifepristone was significantly higher than in rats injected with vehicle. The contractile activity in mifepristone-treated rats remained higher than in control rats, at 12, 24 and 48 h. Fetal viability 36 h after mifepristone injection, when uterine contractions had lasted for 32 h, was not significantly different from fetal viability in rats injected with vehicle, but at 42 h after mifepristone injection, fetal viability was significantly reduced.

In ovariectomized rats, uterine contractile activity at 12, 24, 36 and 48 h, but not at 8 h, was significantly greater than in ovariectomized rats with progesterone replacement (4 mg day−1). Fetal viability at 42 h after the operation, when uterine contractions had lasted for 30 h, was not significantly reduced, but it was significantly reduced at 48 h. When ovariectomized rats had been left to develop uterine contractions for a period before progesterone was injected, deprivation of progesterone and prolonged uterine contractions for about 30 h did not reduce fetal viability or fetal growth determined on day 18, but it did so 3 days later, on day 21. Administration of 5 mg isoxuprine kg−1 twice a day, which suppressed uterine contractions, improved fetal viability in ovariectomized rats at the earlier stage, but not at the later stage. Nevertheless, isoxuprine did improve fetal growth at the later stage in these ovariectomized rats.

It is concluded that increased uterine contractile activity sustained for 32 h or less does not reduce fetal viability, but longer periods of contraction may be the cause of fetal death.

Keywords: fetal viability; fetal growth; uterine contractions; progesterone withdrawal; rat

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W. Arkaravichien and K. E. Kendle

Summary. The minimum progesterone concentration required to maintain the pregnancy was studied by varying doses of progesterone given subcutaneously to rats ovariectomized on Day 8 of pregnancy. Injecting 3 mg progesterone plus 200 ng oestradiol benzoate daily provided serum progesterone values betwen 25·4 ± 7·0 and 35·2 ± 6·2 ng/ml throughout Days 10–19 which were significantly lower than normal levels (P < 0·05), but resulted in 93·6% of fetal survival on Day 19 which was not significantly different from 93·3% in the control group. Injecting 2 mg progesterone plus 200 ng oestradiol benzoate daily gave progesterone values between 13·2 ± 4·6 and 19·0 ± 6·2 ng/ml and could not maintain fetal viability to Day 19 (14·2%, P < 0·05 compared with control group).

Critical times to supplement progesterone in rats ovariectomized on Day 8 or Day 15 were studied by varying the time of progesterone implantation after ovariectomy. Progesterone implants were administered 8, 12 and 24 h after ovariectomy on Day 8 and 24, 36 and 48 h after ovariectomy on Day 15. On Day 8, progesterone replacement could be delayed to 8 h but not 12 h, while on Day 15, progesterone replacement could be delayed up to 36 h but not 48 h after ovariectomy without affecting fetal survival.

Keywords: progesterone; rat pregnancy; abortion; ovariectomy

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Bernadette Lee and K. E. Kendle

Summary. Mouse oviduct calcium content, determined by atomic absorbance after ashing of the tissue, showed a significant fall on Day 2 of pregnancy followed by a significant rise on Day 3. This pattern was altered by administration of reserpine and oestradiol in doses which were shown to alter the rate of egg transport. In-vitro perfusion of the oviduct, capable of maintaining muscular activity and back and forth movement of eggs for 24 h, was associated with lack of forward progressive motion of eggs and by a more rapid increase in tissue calcium levels during incubation than occurred in vivo.

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K. L. Grieve and K. E. Kendle

Summary. The transport of embryos in mouse oviducts incubated in vitro was studied for 16 h. Successful embryo transport occurred in oviducts incubated from Day 2 or Day 3 of pregnancy, and the process was dependent on the availability of calcium from the incubation medium. This indicates that this phase of transport is a result of smooth muscle activity. Embryo transport did not occur in oviducts perfused from Day 1 of pregnancy.