Pharmacologic actions of progestins to inhibit cervical ripening and prevent delivery depend on their properties, the route of administration, and the vehicle

Abstract

Objective: The purpose of this study was to evaluate cervical changes and delivery at term during pregnancy in rats after various progestin treatments.

Study design: Pregnant rats were treated by various routes and vehicles with progesterone, 17-alpha-hydroxyprogesterone caproate (17P), R5020, and RU-486. Delivery time was determined and cervical ripening was assessed in vivo by collagen light-induced fluorescence.

Results: The cervix is rigid in the progesterone injection, 17P, and vaginal R5020 groups vs controls. Vaginal progesterone had no effect. RU-486 treatment softened the cervix during preterm delivery. Only subcutaneous injected progesterone, R5020 (subcutaneous and vaginal), and topical progesterone in sesame and fish oil inhibits delivery. Delivery is not changed by subcutaneous injection of 17P, vaginal progesterone, oral progesterone, and topical progesterone in Replens (Crinone; Columbia Labs, Livingston, NJ).

Conclusion: Inhibition of cervical ripening and delivery by progestins depends on many factors that include their properties, the route of administration, and the vehicle. This study suggests reasons that the present treatments for preterm labor are not efficacious.

Figure 1

Bar graphs showing means ± SD of cervical light-induced fluorescence (LIF) obtained in vivo from nonpregnant (N = 3), pregnant (d13, 15 and 17: N = 12/ group; d19 and d21: N = 11 / group; d22: N = 6) and postpartum rats (pp3, 5 and 7: N = 7; pp10: N = 6). Significant differences (P <0 .05) between groups are marked with different letters.

Figure 2

Bar graphs showing means ± SD of cervical light-induced fluorescence (LIF) obtained in vivo from pregnant rats at different days of pregnancy and postpartum (N = 6/ group) treated with various progestins or vehicle. Figure 2A: Daily treatment with vehicle (controls) or P4 (4 mg, s.c.). Note that delivery is inhibited in the treatment group. Figure 2B: Twice a day treatment with vehicle (controls) or vaginal P4 (15 mg bid). Note that no significant differences are observed at any time between controls vs. treated animals. Figure 2C: Treatment daily with vehicle (controls) or 17P (10 mg, s.c.). Note that significant differences are only observed until day 19 of gestation. Figure 2D: Twice a day treatment with vehicle (controls) or vaginal R5020 (1 mg bid). Note that significant differences are observed only until day 19, but delivery is blocked in the treatment group. Asterisks indicate P < 0.05 compared with controls.

Figure 3

Bar graphs showing means ± SD of cervical light-induced fluorescence (LIF) obtained in vivo from pregnant rats at different days of pregnancy and postpartum (N = 6/ group) treated once on day 16 with vehicle (controls) or RU-486 (3 mg s.c.). Asterisks indicate P <0 .05 compared with controls.

Figure 4

Shown is the percent of animals delivering versus day of pregnancy after various treatments. Figure 4A: Delivery times after daily treatment with vehicle (s.c., controls), P4 (4 mg, s.c.) and 17P (10 mg, s.c.). Note that injections of P4 completely blocked delivery, whereas 17P had no significant effect on delaying term delivery (see also Figure 5). Figure 4B: Percent of animals delivering versus time of delivery following twice a day treatment with vaginal vehicle (controls), vaginal P4 (15 mg bid) and vaginal R5020 (1 mg bid). Note that vaginal R5020 completely blocked delivery, whereas vaginal P4 had no significant effect on delaying term delivery (P >0 .05 compared with controls, see also Figure 5).

Figure 5

Shown is the time of delivery (= hours after 8 a.m. of day 22 of gestation) of pregnant rats treated with vehicles (controls) and various progestins by different routes of administration – injections (s.c.; daily): vehicle: sesame oil; P4 (4 mg); R5020 (2 mg); 17P (10 mg); vaginal (bid): vehicle: Replens^®; P4 (15 mg, Crinone^®); R5020 (1 mg); oral (bid): vehicle: sesame oil or H₂O; P4 (15 mg); topical (bid): vehicle: Replens^®, sesame oil or fish oil; P4 (15 mg). Rats with delayed parturition were sacrificed on day 25. Asterisks indicate P <0.05 compared with controls.