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Objectives: To evaluate acceptability, safety, and continuation rates of centchroman following abortion., Study Design: Prospective, observational study. Following spontaneous/induced abortion, women were offered centchroman, 30-mg tablet twice weekly for first 3 months, then once weekly with 1 year of follow-up., Results: Of 120 women who opted for centchroman, continuation rate was 91% at 12 months. There was one case of user failure and one method failure and 26% had infrequent cycles., Conclusions: Centchroman is safe, effective, has good acceptance, and continuation rate post abortion with infrequent menstrual cycles as the main limiting factor for its continuation., Implications: Centchroman, available in Government scheme for contraception, has good acceptance and continuation rate post abortion. Its inclusion in contraceptive choices offered for postabortion contraception can go a long way in spacing of pregnancies, decreasing repeated unintended pregnancies, unsafe abortions, maternal morbidity, and mortality., Competing Interests: Conflicts of interest statement The authors have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Centchroman, a nonsteroidal oral contraceptive, was evaluated for its hitherto unstudied effect on cardiovascular system, thyroid function and tissue lipid peroxidation in rats., Study Design: Wistar sperm-positive female rats were treated with Centchroman (1.5 mg/kg per day, po) for 10 days and the alterations in serum concentration of thyroid hormones [triiodothyronine (T(3)) and thyroxine (T(4))], insulin, glucose, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phospahatase (ALP) activity, hepatic type-1 iodothyronine 5'-monodeiodinase (5'D) enzyme activity and hepatic, renal, cardiac and serum lipid peroxidation (LPO) were studied. Simultaneously, alterations in endogenous antioxidants [superoxide dismutase (SOD); catalase (CAT) and reduced glutathione (GSH)], relative risk ratio (RR), atherogenic index (AI) and daily rate of food and water consumption were also investigated as supportive parameters., Results: Centchroman administration resulted in the complete inhibition of pregnancy. It increased serum T(4) marginally and HDL-C levels, hepatic SOD, CAT and GSH; cardiac SOD and GSH and renal SOD and CAT activity significantly. However, it reduced LPO in all tissues; concentrations of other serum lipids; AI; RR and activity of ALP., Conclusions: As Centchroman administration did not alter the concentrations of most active thyroid hormone, T(3), serum insulin and glucose, it appears that the drug has no side effect on thyroid function and glucose metabolism. Rather, it possesses cardiovascular and anti-peroxidative benefits.

Introduction: Centchroman (international nonproprietary name: ormeloxifene) is a nonsteroidal selective estrogen receptor modulator, oral contraceptive, anticancer and antiosteoporotic agent that is intended for long-term use by women. In view of the vast clinical applications and interactions of steroidal oral contraceptives with commonly used therapeutic agents, the interaction potential of certain concomitantly administered therapeutic agents was investigated in terms of postcoital contraceptive efficacy (pharmacological) and the pharmacokinetic profile of centchroman in female Sprague-Dawley rats. The coadministered drugs used in the study were ciprofloxacin, cefixime, amoxicillin, metronidazole, amlodipine, atenolol, theophylline, metformin, pioglitazone and glibenclamide., Materials and Methods: The pharmacological activity of centchroman was evaluated in sperm-positive female rats at 1.5 mg/kg, with or without coadministered drugs. Rats were sacrificed on Day 10 postcoitus, and autopsy was performed to check for the presence or absence of implantations. The estrogenic and antiestrogenic activities of centchroman were evaluated in immature ovariectomized rats. Pharmacokinetic interaction was studied in normal female rats with or without coadministered drugs. Serum samples were taken over 120 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of centchroman. Pharmacokinetic parameters were estimated using noncompartmental analysis, and the results were compared., Results: In pharmacological interaction studies, centchroman alone showed a 100% success rate when given alone or in the presence of coadministered drugs. The only exception was amoxicillin coadministration, with 66% rats in the group showing resorbed implantations. Further investigation with amoxicillin in ovariectomized immature rats indicates no alteration in the estrogenic and antiestrogenic profiles of centchroman. In pharmacokinetic interaction studies, most of the therapeutic agents affected the rate and extent of absorption of centchroman. In other pharmacokinetic parameters, clearance (CL) remained unchanged; however, there was decrease in bioavailability (F) and volume of distribution (V(d)) in some situations., Conclusions: The results indicate that there is no direct link between the altered pharmacokinetics of centchroman and the failure of pharmacological effect. The pharmacological interaction with amoxicillin could not be explained on the basis of alteration in the estrogenic and antiestrogenic activities of centchroman, indicating that different mechanisms are involved. The findings, however, suggest that amoxicillin coadministration may result in pharmacological interaction with centchroman and that caution should be taken in clinical practice.

Studies were undertaken to evaluate the influence of estrogen antagonist-cum anti-implantation agent, ormeloxifene, on 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activity and estrogen action in rat uterus during preimplantation period and to examine its ability to induce progesterone receptor (PR) in immature rat model. A group of female rats received orally a contraceptive dose of 1.25 mg/kg of ormeloxifene on Day 1 postcoitum (pc). Rats were sacrificed on Days 3, 4 and 5 pc, and uterine tissues were processed for enzymatic, estrogen receptor and estradiol (E(2)) estimations. Immature ovariectomized rats received ormeloxifene, subcutaneously for 3 days at various doses in the absence or presence of estradiol, and uterine PR levels were measured using (3)H-R5020 as radioligand. Results revealed that ormeloxifene treatment caused a marked increase in enzyme activity of 17beta-HSD on Days 3, 4 and 5 pc as compared to respective controls. Further, total uterine estrogen receptors as estimated by exchange assay showed a noticeable decrease on Days 4 (35%) and 5 (>80%) pc in ormeloxifene-treated groups. The results correlated well with a decrease in tissue E(2) levels. In immature rats, ormeloxifene caused a dose-dependent increase in cytosolic PR levels; ormeloxifene given along with E(2) (0.1 mug) for 3 days caused a significant reduction in concentration of PRs at 10 mug and higher doses. Ormeloxifene also induced (3)H-progesterone (P) uptake by immature rat uterus. However, in the presence of E(2), it significantly reduced (3)H-P uptake. The in vitro competitive binding experiments did not reveal any displacement of (3)H-R5020 either by ormeloxifene or by its hydroxy derivative from PR. The results suggest that in addition to its competitive antagonism at estrogen receptor level, ormeloxifene enhances the inactivation of intracellular E(2) to estrone, a biologically less active form, thus declining estrogen receptor pool. Moreover, it causes indirect anti-progestational effects in the uterus by virtue of its anti-estrogenic profile rather than by blocking the PRs.

Among the 10 commonly used therapeutic agents investigated, concurrent oral administration of tetracycline (140 mg/kg) twice daily on Days 1-5 post-coitum (pc) interfered with the post-coital anti-implantation activity and almost completely abolished estrogen antagonistic activity of the single anti-implantation (1.5 mg/kg, orally) dose of dl-ormeloxifene administered on Day 1 pc, resulting in the occurrence of resorbed implantations in 50% of the females. However, no such interaction was evident when tetracycline was administered intramuscularly or when ormeloxifene was administered at twice its anti-implantation dose. There was no effect of ormeloxifene and/or tetracycline treatment on serum estradiol and progesterone levels, and all animals presented apparently normal corpora lutea. Ormeloxifene administered per se inhibited aminopyrine-N-demethylase (AD), glucose-6-phosphate dehydrogenase (G-6-PDH) and glutathione-S-transferase (GST) in the liver on the day of maximal endometrial receptivity, which was prevented by tetracycline co-administration. Aniline hydroxylase and AD were not detected in small intestine or uterus in vehicle control or any of the treatment groups. There was, however, no effect of ormeloxifene plus tetracycline treatment on serum total alkaline phosphatase activity. Findings suggest that interference with anti-implantation action of ormeloxifene by tetracycline might be due primarily to the almost complete abolition of its estrogen antagonistic activity at the uterine level, effected by decreased bioavailability of ormeloxifene and/or its active metabolite(s) by altered enterohepatic recirculation because of the effect on gut microflora. This might alternatively be related to an increased rate of its metabolism and elimination from the system via prevention of ormeloxifene-induced inhibition of hepatic AD, G-6-PDH, and GST, which, by effecting a decreased rate of metabolism, might be responsible for prolonged (approximately 120 h) duration of estrogen antagonistic/anti-implantation action of ormeloxifene in this species.

To assess the alleged estrogenic and antiestrogenic profile of centchroman, a phenotypical response was studied in native uterine cells or migrant blood cells in adult ovariectomized rats under the influence of estradiol-dipropionate (EDP) and centchroman (CC) given per se and together. Histologic observations were divided arbitrarily into the following regions: luminal epithelium, superficial and deep stroma, and the two layers of muscularis. Glandular cell proliferation, mitoses, and vascularity were examined additionally. It was found that CC per se stimulated luminal epithelial cell height and glandular cell proliferation better than EDP. Leukocytic infiltration and vascularity were also more pronounced in the uteri of CC-treated rats. Furthermore, except for a slight reduction in glandular cell size and edematous condition of circular muscle layer, the changes remained unaffected after conjoint treatment of CC and EDP. The observations revealed that some of the nongenomic responses, elicited by the rat uterus after CC treatment, seem to be unrelated to the hormonal attributes of the molecule.

The period of maximal endometrial sensitivity in the rat was characterized by high alkaline phosphatase activity in uterine luminal and glandular epithelium and endometrial stroma. The activity in endometrial stroma increased following decidualization. Pinopod development on the endometrial surface was first observed during the presensitivity period. Their number increased, apparently more so on the antimesometrial rather than the mesometrial segment of the uterus, on the day of maximal sensitivity. Inhibition in endometrial sensitivity by single anti-implantation (1.25 mg/kg, po) dose of centchroman on day 1 post-coitum (p.c.), although it did not affect alkaline phosphatase activity on days 2 and 3 p.c., caused complete inhibition in its activity in uterine luminal and glandular epithelium and pinopod development on days 4 and 5-coinciding, respectively, with time of entry of preimplantation embryos into the uterus and period of maximal endometrial sensitivity in this species. Significant decrease in enzyme activity was also evident in the entire endometrial stroma and myometrium, except blood capillaries, on these days. In comparison, prevention of entry of native embryos into the uterus by placing a ligature at the utero-tubal junction had no effect on pinopod development, but caused marked decrease in enzyme activity in luminal and glandular epithelium only during the immediate postimplantation period. The uterine lumen on the day of maximal sensitivity in centchroman-treated rats appeared highly distended and was lined with tall columnar epithelium, in comparison to low cuboidal epithelium in controls. The findings demonstrate: (a) a correlation between uterine luminal epithelial alkaline phosphatase activity and endometrial sensitivity; (b) complete inhibition in enzyme activity in luminal and glandular epithelium following centchroman treatment might be related to altered permeability characteristics of epithelial cells, which together with the absence of pinopods and highly distended uterine lumen on the day of maximal sensitivity, suggest inhibition of endocytosis/pinocytosis of luminal fluid, luminal closure, apposition of blastocyst trophoblast to luminal epithelium, and secretory activity of glandular epithelium; (c) pinopod development on the endometrial surface was independent of presence of viable blastocysts in utero; and (d) complete absence of pinopods suggests lack of endometrial sensitivity, but their presence might not necessarily indicate a sensitized endometrium in the rat.

Effect of antiestrogen ormeloxifene on progesterone-induced development of giant mitochondria in uterine glandular epithelial cells in ovariectomized adult Sprague-Dawley rats was investigated. Antiestrogen tamoxifen and antiprogestin onapristone were used for comparison. Well-formed giant mitochondria were observed in uterine glandular epithelial cells in rats treated with progesterone (20 mg/kg, subcutaneous [SC] per se for three consecutive days. In rats primed with estradiol-17 beta (0.5 micrograms/day, s.c.) on days-2 and -1 before progesterone treatment, there was, in addition, a marked increase and distension of smooth endoplasmic reticulum (SER) and Golgi complex, in comparison to extensive rough endoplasmic reticulum (RER) and polyribosomes in progesterone per se treated rats. Cytological picture in rats receiving single (1.25 mg/kg, day 1, p.o.) or multiple (0.25 mg/kg, days 1-3, p.o.) anti-implantation doses of ormeloxifene showed marked reduction in glandular epithelial cell height, luminal surface microvilli, RER, polyribosomes and cytoplasm:nucleus ratio, straightening of intercellular membranes, and interdigitation of basement membrane. Mitochondria were of normal size and nuclei were heterochromatic. Inhibition in the case of tamoxifen (0.1 mg/kg, days 1-3, p.o.) appeared partial and rare giant mitochondria with degenerating cristae and outer membranes were apparent. Onapristone (10 mg/kg, day 1, s.c.), in addition to inhibiting development of giant mitochondria, caused extensive vacuolization and distension of intercellular membranes in glandular epithelial cells.

Time-related estrogen antagonistic action of a single oral contraceptive (1.25 mg/kg) dose of the triphenylethylene antiestrogen centchroman was determined in ovariectomized immature rats. Tamoxifen and nafoxidine were used for comparison. A single oral administration of centchroman followed by three doses of estradiol-17 beta (1 microgram/d, s.c.) caused significant dose-dependent inhibition in estradiol-17 beta-induced increase in uterine weight and nuclear and cytosolic estrogen receptors. But the inhibition at antiimplantation dose was evident only if estradiol-17 beta treatment was initiated not later than 48 h post-antiestrogen. Alternatively, when antiestrogen treatment was followed by a single dose of estradiol-17 beta between days 2-7, a synergistic action, typical of antiestrogens possessing weak estrogen agonistic activity, was observed. In immature rats in which a condition mimicking preimplantation was produced by estradiol-17 beta (0.5 microgram/d, s.c.) priming on days -2 and -1, followed by progesterone (1 mg/d, s.c.) and an endometrial sensitizing dose (0.5 microgram/d, s.c.) of estradiol-17 beta at 1600 h on day 4, anti-implantation dose of centchroman administered on day 1, too, failed to inhibit uterine weight gain induced by sensitizing dose of estradiol-17 beta, but caused marked inhibition in endometrial sensitivity to a deciduogenic stimulus and decidualization and weight gain of traumatized uterine horn 96 h post-traumatization over non-traumatized horn was only about 150% (725% in controls). Inhibition in endometrial sensitivity and decidualization was evident when the interval between antiestrogen treatment and sensitizing estradiol was < 126 h. Pinopods were present on endometrial surface on day 5 whether or not priming and/or sensitizing doses of estradiol were administered, but decidual response was mild if either of these doses of estradiol-17 beta was deferred. Findings suggest that: (a) duration of antiestrogenic action of single anti-implantation dose of centchroman in rat was about 126 h, which in ovariectomized immature rats was evident only when a condition mimicking preimplantation was produced and the antiestrogenic response was based on inhibition in estradiol-induced endometrial sensitivity and not uterine weight gain; (b) priming as well as sensitizing estrogen were essential to get optimal decidual responses; (c) appearance of pinopods on endometrial surface may not be related to endometrial sensitivity; and (d) tamoxifen and nafoxidine appear slightly longer acting with duration of antiestrogenic action of approximately 150 h.

The present study reports the modulatory influence of oral contraceptive formulations, Ovral (0.05 mg ethinylestradiol plus 0.5 mg norgestrel per pill), Noracycline (0.05 mg ethinylestradiol plus 0.1 mg lynestrenol per pill), Pearl (0.03 mg ethinylestradiol plus 0.30 mg norgestrel) and Centchroman (30 mg), on the growth and developmental pattern of murine mammary epithelium in normal as well as ovariectomised mice. Oral treatments of ovariectomised mice for 15 days with doses D1 (1/5th of a pill) and D2 (1/10th of a pill) of Ovral, Noracycline and Pearl enhanced the diameter of the terminal end buds (TEBS) and lateral buds (LBS) significantly. The increase in the diameters of TEBS and LBS on treatment with similar doses of Centchroman were not much significant. Hence, it may be concluded from the present study that the growth and development pattern of mammary epithelium can be modulated by treatment with oral contraceptives Oral, Noracycline, Pearl and Centchroman which is indicated by the increase in the diameters of TEBS and LBS.

The effect of three compounds (clomiphene citrate, centchroman, embelin) and plant-derived methanolic extracts (Abutilon indicum and Butea monosperma) was studied on uterotropic and uterine peroxidase activities in ovariectomized rats. It was observed that these two parameters were highly correlated in response to treatment with these test materials and also to estradiol. It was suggested that the uterine peroxidase assay could be utilized as a biochemical parameter in the screening of new antifertility agents for their estrogenic/antiestrogenic properties.

Effect of long-term Centchroman (3,4,-trans-2,2-dimethyl-3-phenyl-4-p-(beta-pyrrolidinoethoxy)-phe nyl)-7-methoxy chroman) treatment on some estrogen-sensitive biochemical parameters in the genital organs of female rhesus monkey was studied. Centchroman treatment did not demonstrate any consistent pattern of stimulation or inhibition in any of the estrogen-sensitive biochemical parameters. However, glycogen recorded a gradual decline in uterus, cervix and vagina. The results thus indicate that Centchroman evoked a mixed response probably due to manifestations of both estrogenic and antiestrogenic properties.

Effect of weekly oral administration of Centchroman (3,4-trans-2, 2-dimethyl-3-phenyl-4-(p-(beta-pyrrolidinoethoxy)-phenyl)-7-met hoxychroman) at 1 and 2.5 mg/kg for 12 months on plasma estradiol, progesterone, luteinizing hormone and follicle stimulating hormone of female rhesus monkeys was studied. Centchroman administration at both doses did not disturb the menstrual pattern of rhesus monkeys except for a prolongation of the first treatment cycle. The subsequent cycles were of normal duration. The general pattern of plasma estradiol, progesterone, luteinizing hormone and follicle stimulating hormone was not affected by Centchroman treatment. The basal and peak levels were similar in pretreatment, control and treatment cycles. The results clearly indicate that Centchroman treatment up to 1 year does not affect the hypothalamo-pituitary-ovarian axis in female rhesus monkeys.