Centchroman was administered to rats in relation to luteal phase nidatory estrogen secreted between 21.00 on day 4 and 10.00 on day 5 of pregnancy. A single oral dose of 1.25 mg/kg before the secretion of nidatory estrogen, i.e. until 21.00 on day 4, prevented implantation in 100% of the rats without altering plasma estradiol or progesterone concentration. Administration of a dose of up to 62.5 mg/kg at 10.00 on day 5 even failed to inhibit implantation, but caused dose-dependent resorption of implantations. Resorption of all implantations at a dose of 62.5 mg/kg was associated with a decrease in circulating progesterone levels, but was only partially reversed by progesterone or progesterone + estrone supplementation. Apparently normal morulae and blastocysts recovered between days 4 and 10 from rats treated with anti-implantation doses before release of nidatory estrogen, when transferred to the uteri of control rats exhibited lower pregnancy, implantation and development rates with increasing confinement in the genital tract of treated donors. None of the embryos recovered from control or centchroman treated females implanted in the uteri of treated rats. Centchroman administration on day 1, but not on day 5, abolished endometrial receptivity to an artificial stimulus for decidualization. All term fetuses were apparently normal and their weight comparable to that of control fetuses. The study provides evidence of post-implantation fetal resorption, occurring primarily between days 10 and 19 post-coitum, in rats treated with a potent antiestrogen before or immediately after the prenidatory estrogen secretion. This was not related to altered ovarian function and the decreased plasma progesterone concentration on day 19 after a higher dose of the compound was secondary to resorption of all implantations.
MM Singh, SC Chauhan, RN Trivedi, SC Maitra and VP Kamboj
Singh MM, Chauhan SC, Trivedi RN, Maitra SC, Kamboj VP. Correlation of pinopod development on uterine luminal epithelial surface with hormonal events and endometrial sensitivity in rat. Eur J Endocrinol 1996;135:107–17. ISSN 0804–4643
Intrinsic role of preovulatory and nidatory estrogen and progesterone and presence of viable blastocysts in utero in pinopod development on the uterine luminal epithelial surface and correlation between time of their development and onset of endometrial sensitivity were investigated. In adult rats, pinopods were observed on the entire epithelium even before secretion of nidatory estrogen, i.e. at 14.00 h on day 4 post-coitum (p.c.). Apparently, their number increased, more so on the antimesometrial than the mesometrial side, at 10.00 h on day 5, but were fewer and mostly collapsed at 10.00 h on day 6. Pinopods on day 4 were located within epithelial depressions and foldings, but protruded from the surface on days 5 and 6. Normal pinopods were also present on day 8 p.c. in rats under delayed implantation, but an implantation-inducing dose of estradiol-17β administered about 18 h earlier caused their collapse like that on day 6 in intact rats. Development and appearance of pinopods in intact or delayed rats was unaffected when native preimplantation embryos were prevented from entering the uterus. Normal pinopods were seen in immature rats receiving progesterone for at least 3 days or cyproterone acetate for 4 days, but not after estradiol alone. In animals receiving progesterone or priming/sensitizing estradiol in addition to progesterone, the decidual response was suboptimal, irrespective of the presence of pinopods on the day of stimulation. In animals in which a condition mimicking preimplantation had been produced by suitable hormone supplementation, optimal endometrial sensitivity and decidual response were elicited, even though most pinopods appeared collapsed, resembling those on day 6 in intact rats and about 18 h after estradiol in implantation-delayed rats. Findings confirm that pinopod development on uterine luminal epithelium was dependent on progesterone alone and demonstrate that: (i) preovulatory (priming) or nidatory (endometrial sensitizing) estrogen or viable blastocysts in utero have no role in their development. Nidatory estrogen, instead, appears to limit pinopod development by causing their collapse; (ii) pinopod development/presence on the endometrial surface might indicate the uterus coming into a period of sensitivity rather than actually being in it and might thus serve as a useful marker of "transfer window" rather than "implantation window"; (iii) in the rat, pinopod development might serve as an alternate assay for evaluation of progestational activity of newer test agents.
MM Singh, Division of Endocrinology, Central Drug Research Institute, Lucknow 226 001, India