Effect of CDRI-85/287, a potent antiimplantation agent on uterine endometrial dimensions and peroxidase levels in rat.

CDRI compound 85/287 a potent estrogen antagonist and antiimplantation agent in rat was studied to elucidate its mechanism of action. In ovariectomized rats 85/287 treatment antagonized estrogen stimulated uterine volume density, eosinophil leucocyte infiltration, stromal mitotic cell number and peroxidase activity. In parallel experiments in pregnant rats, uterine peroxidase activity also decreased significantly as compared to controls on day 5 post-coitum. The results show that 85/287 exerts its antiimplantation activity by inhibition of responses to estradiol action.

Seasonal variations in Sertoli and germ cell marker enzymes in testis of rhesus and bonnet monkeys.

Variations in specific activities of the marker enzymes of Sertoli and germ cells during breeding (November-December) and non-breeding (May-June) seasons were investigated in rhesus and bonnet monkeys maintained under laboratory conditions. The marker enzymes selected for testicular cells were-Sertoli cells: beta-glucuronidase, gamma-glutamyl transpeptidase; pre-meiotic germ cells: glucose 6-phosphate dehydrogenase, malate dehydrogenase, alpha-glycerophosphate dehydrogenase; mature germ cells: LDH-X, sorbitol dehydrogenase. Results have indicated significant seasonal variation in marker enzymes only in rhesus testis. Marker enzymes of Sertoli cell increased while those of germ cell decreased significantly during non-breeding season. Marker enzymes of mature germ cells were affected much more drastically than those of the pre-meiotic germ cells.

Response of the postnatal rat epididymis to estrogen & antiestrogens.

The effect of androgen and estrogen antagonists on estrogen induced responses in the epididymis of rat was studied. Estradiol benzoate administered to male rates on day 5 of life increased the epididymal weight, absolute volume density of fibromuscular stroma and its eosinophilic leucocyte numbers. Testosterone administration (day 5 life) alone did not have any stimulatory effect on the epididymis as an organ or its peroxidase activity on days 15 or 20 of life. On the other hand, testosterone/85/287 negated estradiol induced increase in the absolute volume density, eosinophilic leucocyte accumulation and peroxidase activity. Tamoxifen (Tam) with inherent estrogenic activity acted both as an agonist and an antagonist. Results of present studies support the contention that nonsteroidal antiestrogens (CDRI-85/287 and Tam) can modulate estradiol induced epididymal responses during the postnatal period of male rat.

Androgenic regulation of glycolytic and HMP pathway in epididymis and vas deferens of rhesus monkey.

The androgenic regulation of the eleven enzymes of glycolytic pathway and two key enzymes of HMP pathway was studied in the initial segment, caput, corpus and cauda regions of the epididymis and in the vas deferens of rhesus monkey. The specific activities of enzymes were expressed as units of activity per mg DNA. Results in control animals indicate a marked difference in energy metabolism of epididymis and vas deferens. However, the epididymal duct itself did not show much regional variation in enzyme activities along its length. All the enzymes of the two pathways studied showed significant reduction after castration, the regulatory enzymes being affected more severely. On treatment with exogenous dihydrotestosterone, most of these enzymes showed stimulation in castrated monkeys, but none of them could be restored to normal level. The stimulation of these enzymes on treatment with exogenous dihydrotestosterone varied along the epididymal duct itself being maximum in the initial segment and minimum in the cauda region. The changes in the vas deferens were less marked as compared to the epididymis following castration and androgen replacement.

CDRI-85/287: studies on competition to estrogen binding sites in the immature rat uterus.

Ability of compound CDRI-85/287, a new nonsteroidal antiestrogen with negligible inherent estrogenicity, to inhibit uptake of 3H-estradiol (3H-E2) by the immature rat uterus in vivo was investigated. Different doses of 85/287 were administered either intraperitoneally 30 min before 3H-E2 or orally 1 and 6 hr before 3H-E2. A dose dependent inhibition in 3H-E2 uptake was observed after administration of the compound by either route and was 69% at 50 micrograms/rat ip dose and 80% at 2.5 mg/kg po dose. In in vitro competitive binding assay, however, the compound showed poor affinity (RBA 0.42% of estradiol-17 beta) for cytosolic estrogen receptors. Considering the potent anti-estrogenic as well as anti-implantation efficacy of the compound, its action in vivo appears to be mediated via its active metabolite(s).

Effect of efferentiectomy on enzymes of glycolytic pathway, HMP pathway and TCA cycle in epididymis and vas deferens of rhesus monkey.

The importance of exocrine secretions of testis in the regulation of energy metabolism of the epididymis and vas deferens was examined in rhesus monkeys by performing efferentiectomy. At autopsy the epididymis was divided into initial segment, caput, corpus and cauda portions to make an account of regional differences, if any. Eleven enzymes of glycolysis, two key enzymes of HMP pathway and seven enzymes of TCA cycle were assayed in the epididymal segments and vas deferens of control (intact) and experimental (efferentiectomised for 90 days) monkeys. The results indicate that while anaerobic energy metabolism (glycolysis and HMP pathway) is sensitive to efferentiectomy chiefly in the proximal regions of epididymis, the oxidative pathway (TCA cycle) is dependent on testicular exocrine secretions throughout the length of epididymis, as well as in the vas deferens. Since all androgen-sensitive enzymes do not regress after efferentiectomy, it is suggested that unidentified exocrine factors of testis may have role in regulating energy metabolism in the epididymis and vas deferens.

Duration of antiestrogenecity of compound CDRI-85/287: a new orally active nonsteroidal antiimplantation agent.

Duration of antiestrogenic and antiimplantation action of CDRI-85/287, (2-(4-(2-N-piperidino)ethoxy phenyl)-3-phenyl(2H)benzo(2)pyran), was studied in rat. Pretreatment of ovariectomized immature rats with this compound caused translocation of cytoplasmic estrogen receptor (ER) to the nucleus and a marked depletion of cytoplasmic ER pool resulting in a nonresponsive state of the uterus to subsequent estrogen administration until day 4. While in rats pretreated with estradiol, increased cytoplasmic ER level made the uterus responsive to a second injection of estrogen. In the delayed implantation model, 85/287 pretreated rats were given estrone on days 4, 5 or 6 post-antiestrogen treatment. No implantations were observed after estrone administration on day 4, but were present when estrone was given on days 5 or 6. Summation of these results suggests the duration of action of 85/287 to be 3-4 days in rat.

Post-coital antifertility activity of the marine plant, Achrostichum aureum L. in rat.

The ethanolic extract of A. aureum and its fractions were evaluated for postovulatory antifertility activity in female rats. The water soluble fraction of ethanolic (95%) extract prevented (100%) pregnancy when administered to female rats on days 1-7 postcoitum. This fraction was found devoid of both estrogenic and antiestrogenic activities.

Effect of antiandrogens on some key enzymes of glycolysis in epididymis and ventral prostate of rat.

Effect of three antiandrogens: cyproterone acetate (5 mg/day, sc), flutamide (5 mg/day, sc) and STS-557 (5 mg/day, po) and an estrogen, estradiol dipropionate (5 micrograms/day, sc) on some key enzymes of carbohydrate metabolism was investigated in adult rat epididymis and ventral prostate. Antiandrogens were administered for 21 days and estrogen for 14 days. All of them caused a significant decrease in the weight of epididymis, seminal vesicles and ventral prostate. A significant decrease in the specific activities of enzymes (hexokinase, phosphofructokinase, aldolase, glyceraldehyde phosphate dehydrogenase, pyruvate kinase, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase) occurred only in the organs of estrogen treated rats; activities of some of the enzymes were lowered also in the prostate of STS-557 treated rats. Flutamide and cyproterone acetate were ineffective in this regard. The possible factors responsible for the ineffectiveness of synthetic antiandrogens in influencing epididymal metabolism are discussed.