The effect of flutamide, a non-steroidal antiandrogen on the growth and secretory function of the epididymis of rat during transition from prepubertal age (35 days old) to puberty (50 days old) was investigated. The results showed that the antiandrogen interfered with the growth of all the genital organs accompanied by a marked reduction in the secretory function of the epididymis as revealed by lowered levels of sialic acid and glycerylphosphorylcholine. These findings are discussed in relation to our previous observations in adult rats.

Ethanolic extract of Ferula assafoetida and chloroform fraction of Melia azedarach, both devoid of estrogenic activity, were examined for their pregnancy interceptive property. Treatment of rats from days 1 to 7 of pregnancy with either of the plant extracts resulted in pregnancy failure in about 65-85% of the animals. The possible role of energy metabolism in the antifertility action was investigated by measuring changes in activities of the key enzymes of carbohydrate metabolism in uterus on day 7 of pregnancy. It was observed that on the day 7 of pregnancy, one key enzyme of glycolytic pathway (phosphofructokinase) was significantly reduced in the uteri of treated rats as compared to controls. Hexosemonophosphate pathway also appeared to be sensitive to treatment with the plant extracts and showed an inhibitory effect on the enzyme activities of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. Oxidative energy metabolism through tricarboxylic acid cycle, which is considered to be the main source of energy to the uterus at this stage, was maximally affected by the treatment with several enzymes showing significant inhibition. The two plant materials appeared to interrupt the latter metabolic pathway more significantly. It is thus concluded that plants lacking phytoestrogens may intercept pregnancy by their ability to disrupt energy metabolism in rat uterus during implantation, especially the oxidative pathway. (C) 2004 Elsevier Inc. All rights reserved.

Some suitably substituted acrylophenones, quinolines and dithiocarbamate were synthesized as new generation, non-detergent spermicides and were studied for their mechanism of action in comparison with various known spermicides belonging to several different classes of chemical compound. Nonoxynol-9, benzalkonium chloride, Sapindus saponins, verapamil, emetine and tartaric acid were used as reference molecules to study the effect of new spermicides on human sperm motility parameters (using computer-assisted semen analyzer), plasma membrane integrity, lipid peroxidation and defense system against reactive oxygen species (ROS). Results have indicated that sperm plasma membrane remains the primary site of action of most of the spermicides, though the effect may be predominantly on the physiological integrity rather than the structural integrity in case of the new compounds. Lipid peroxidation may play an important role in disrupting sperm membrane physiology that may or may not be accompanied with a detrimental effect on the defense system of the human spermatozoa against the ROS.

Daily sperm production (DSP) rate was estimated in adult male rhesus and bonnet monkeys to evaluate seasonal changes in the gametogenic activity of the testes. Three monkeys of each species were castrated during breeding and non-breeding seasons and DSP rate was estimated by enumerating the homogenization-resistant spermatid nuclei of steps 13 and 14. Results indicated a significant reduction in the DSP rate per testis during the non-breeding season in two species, along with a marked decline in the testis weight. However, the gametogenic capacity of seminiferous tubules did not appear to be markedly affected during non-breeding season, as the DSP rate per gram parenchyma of testis was only marginally reduced. The seasonal changes in DSP were much more pronounced in the rhesus than in the bonnet monkey. The feasibility of circanual rhythm in DSP of sub-human primates to form a baseline for the study of reproductive function in male is discussed.

With a view to elucidating the hormonal control of decidualization in rhesus monkey, we studied the effects of CDRI-85/287, a potent anti-oestrogen, on endometrial steroid receptors in vivo and in vitro. Compound 85/287 was administered (i.m.) on days 8, 9 and 10 of steroid treatment cycle at a dose of 15 mg/monkey. Deciduoma was induced on day 16. Histological examination of endometrial tissue on days 24 and 30 of the cycle showed an apparent inhibition in uterine epithelial and subepithelial decidual cell plaque formation and a decrease in leukocytic infiltration into the stroma in anti-oestrogen-treated animals. As observed on day 24, a significant decrease in progesterone receptors (PR) (nuclear + cytosolic) was observed in the 85/287-treated group, whereas oestrogen receptor (ER) content remained unaltered. On day 30 total ER as well as total PR content was markedly reduced in treated animals. In-vitro results clearly demonstrated a competitive antagonism of 85/287 at the ER level only. The results are discussed in relation to the histological changes and modulation of steroid receptors, thereby suggesting the decidualization inhibitory activity of anti-oestrogen molecule 85/287 in primate species.

CDRI 84/35, a potent nonsteroidal antispermatogenic agent, causes total sterility in rats by directly acting on germ cells while having no effect on Sertoli/Leydig cells. This study was conducted to evaluate the effect of the compound on gametogenic activity of testes and to identify stages of spermatogenesis that were affected. Adult male rats administered either compound 84/35 at minimum effective dose or estradiol (5 micrograms) or water only were killed on days 22, 41, and 64 of the treatment period to evaluate the effect on spermatid, spermatocyte, and spermatogonial stages, respectively. Daily sperm production (DSP) was measured employing a homogenization technique. Results showed a decline in testis weight and DSP with a drastic reduction (approximately 95%) in DSP in 84/35-treated rats on day 41 of the treatment period. Estradiol was more potent in reducing the testis weight; however, 84/35 had an edge over estradiol in reducing the DSP. After withdrawal of treatment for 120 days, a phenomenal recovery (> 90%) in DSP per gram parenchyma was noted in 84/35-treated animals. Results indicate a direct effect of estradiol on spermatogonia, whereas 84/35 seems to affect the spermatocyte stage.

A study was undertaken to estimate the activities of the key enzymes of glycolysis, the pentose phosphate pathway and the tricarboxylic acid (TCA) cycle in purified rat spermatocytes and spermatids, which have been shown to die in glucose-containing medium and require lactate/pyruvate for maintaining normal ATP concentrations. The aim was to elucidate the changes in the glycolytic and oxidative potential of germ cells undergoing meiosis. Pachytene spermatocytes and round spermatids from adult rat testis were purified to approximately 90% purity by trypsin digestion followed by a combination of centrifugal elutriation and Percoll density gradient centrifugation. After the purity and viability of these cells had been established, their contents of hexokinase, phosphofructokinase, lactate dehydrogenase (LDH) and LDH-X of glycolysis, glucose 6-phosphate dehydrogenase of the pentose phosphate pathway and citrate synthase, aconitase, malate dehydrogenase and 2-oxoglutarate dehydrogenase of the TCA cycle were estimated. These enzymes were also estimated in epididymal spermatozoa for comparison with the testicular germ cells. The results indicate greater activity of glycolytic and pentose phosphate pathway enzymes in spermatocytes than in spermatids, which exhibited greater activity of TCA cycle enzymes than the former. The difference in activity was statistically significant for most of the enzymes studied. In contrast, spermatozoa exhibited markedly greater activity of glycolytic enzymes and significantly lower activity of pentose phosphate pathway and TCA cycle enzymes than did the testicular germ cells. We conclude that the unusual dependence of spermatids exclusively on lactate may be due to their lower glycolytic potential, whereas spermatocytes with comparatively greater glycolytic activity have an intermediate dependence on lactate and are therefore able to utilise lactate, pyruvate, or both, while retaining a better ability to utilise glucose. Spermatozoa with the greatest glycolytic potential and the lowest TCA cycle activity appear to be 'programmed' to utilise exclusively glucose/fructose for energy.

Studies with 85/287, a potent nonsteroidal antiestrogen/antiimplantation agent were taken up. In this paper we report alterations in uterine morphometric measurements and estrogen/progesterone receptor levels under the influence of this compound. Results showed 32% decline in stromal absolute volume density on day 5 post-coitum (p.c.) only, whereas eosinophilic leucocyte number decreased both on days 3 and 5 p.c. (41%) in treated rat uterus. Epithelial mitotic activity showed complete cessation both in control and treated rats on day 5 p.c. Under the influence of the compound both cytosolic and nuclear estrogen receptor (ERc and ERn) levels decreased on day 3 p.c., but on day 5 p.c. ERn increased significantly. A significant increase was however noticed in progesterone nuclear receptors (PRn) on day 5 p.c. On the whole our studies showed overall significant changes in uterine morphometric measurement/estrogen and progesterone receptor levels during the preimplantation period in rat under the influence of compound 85/287, causing asynchrony of events and thus failure of implantation.

To assess the lipid metabolising potential of testicular germ cells undergoing meiosis, spermatocytes and spermatids were isolated from adult rat testis and purified by centrifugal elutriation followed by density gradient centrifugation. Seven key enzymes of lipid metabolism (namely beta-hydroxybutyrate dehydrogenase, carnitine acetyl transferase, ATP citrate lyase, hydroxyacyl-CoA dehydrogenase, glycerol 3-phosphate dehydrogenase, acetyl-CoA carboxylase and long chain acyl-CoA synthetase) were assayed in cell homogenates. The results indicated that germ cells possess the key enzymes for de novo synthesis and oxidation of fatty acids. The significant increase in activities of anabolic enzymes and decrease in activities of catabolic enzymes in post-meiotic germ cells indicated a shift in lipid metabolism towards fatty acid synthesis during meiosis. Long chain acyl-CoA synthetase activity was not detected in the two cell types. The study indicates a major reorganization of fatty acid turnover during meiosis with equilibrium shifting in favour of synthesis.

Recent studies have indicated that estrogen has a stimulatory influence on the male reproductive tract. Evidence includes the presence of measurable levels of estrogen in the circulation, retention of exogenous estrogen, and presence of estrogen receptors in the male accessory sex organs during prepubertal life. In the present study, estrogen antagonists (CDRI-85/287 and centchroman) have been used to examine this concept by antagonising estrogen action at critical stages in the life in rat. Centchroman or 85/287 administration to 14 day old rats for 7 days did not alter gonadal or accessory organ weight. In contrast, in 21 day old castrated rats, treatment with either compound from day 28-35 of life stimulated an increase in all organ weights. When administered to normal rats during the critical phase of transition, i.e. days 30-60 of life, both testis and accessory organs showed an increase in weight. In contrast castrated rats treated with estrogen alone or in combination with 85/287 from days 37-45 of life and sacrificed on day 46 did not show any change, but 85/287 per se markedly reduced the weight of accessory organs. In adult castrated rats, the potency of DHT as a promoter of growth was potentiated by estradiol. Compound 85/287 negated the estradiol-induced increase. Glycerylphosphorylcholine (GPC) and sialic acid levels showed about 100% increase, with both high and low doses of 85/287 (treated from 30-60 days of life), However, centchroman (CDRI-67/20) was less potent in this regard. The effect of estrogen antagonists in relation to epididymal physiology during different phases of life in the rat is discussed.

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.

Marker enzymes of Sertoli and germ cells were estimated to study the mechanism of action of antispermatogenic compound CDRI 84/35 in adult male rat testis. Animals were killed after 22, 41, and 64 days of treatment with antispermatogenic dose of CDRI 84/35 in order to evaluate the effect of the compound on spermatid, spermatocyte, and spermatogonial stages, respectively. Studies were also extended to a recovery period of 90 days. Results indicate a direction action of the compound on germ cells, with no apparent effect on Sertoli cells. Studies also show a massive depletion of postmeiotic germ cells after the treatment, with some damage to premeiotic germ cells as well. Reversibility of the compound was partial, with the marker enzymes of pre-and postmeiotic germ cells not being restored to control levels after withdrawal of treatment. (C) 1997 Elsevier Science Inc. All rights reserved.

Marker enzymes of Sertoli and germ cells were estimated to study the mechanism of action of antispermatogenic compound CDRI in adult male rat testis. Animals were killed after 22, 41, and 64 days of treatment with antispermatogenic dose of CDRI in order to evaluate the effect of the compound on spermatid, spermatocyte, and spermatogonial stages, respectively. Studies were also extended to a recovery period of 90 days. Results indicate a direction action of the compound on germ cells, with no apparent effect on Sertoli cells. Studies also show a massive depletion of postmeiotic germ cells after the treatment, with some damage to premeiotic germ cells as well. Reversibility of the compound was partial, with the marker enzymes of pre- and postmeiotic germ cells not being restored to control levels after withdrawal of treatment.

Marker enzymes of Sertoli and germ cells were estimated to study the mechanism of action of antispermatogenic compound CDRI 8435 in adult male rat testis. Animals were killed after 22, 41, and 64 days of treatment with antispermatogenic dose of CDRI 8435 in order to evaluate the effect of the compound on spermatid, spermatocyte, and spermatogonial stages, respectively. Studies were also extended to a recovery period of 90 days. Results indicate a direction action of the compound on germ cells, with no apparent effect on Sertoli cells. Studies also show a massive depletion of postmeiotic germ cells after the treatment, with some damage to premeiotic germ cells as well. Reversibility of the compound was partial, with the marker enzymes of pre- and postmeiotic germ cells not being restored to control levels after withdrawal of treatment.

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.

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.

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Oxiranes obtained by regioselective O-alkylation of 2-(substituted-benzyl)butane-1,4-diols have been used as starting materials for the preparation of alkanals, azido and aminoalkanol derivatives (4, 5 and 6-9). All the new compounds synthesized have been evaluated for their spermicidal activity. Compounds 4c, 7b and 8a show spermicidal activity at 0.05, 1.0 and 1.0% concentration respectively in Sander Cramer's assay.

A number of beta-aminoketones have been synthesised by reaction of pyrrolidine/piperidine/piperazine/4-methylpiperidine/morpholine with 6-methoxy-tetralone (1)/5-methoxy-1-indanone (2)/6-ketoestradiol-17 beta-acetate-3-methyl ether (3) under Mannich reaction conditions. The Mannich bases 8, 9, 12, 13 on reduction give the corresponding hydroxy compounds (16-19). All the compounds have been screened for their spermicidal activity. Compounds 4 and 14 show spermicidal activity at 0.1 and 0.5% concentrations, respectively in Sander Cramer's assay.