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Biomedical subjects

I F Lau

Publications and source records attributed to I F Lau.

At least 19 recordsLinked to original sources

Effects of RMI 12,936 on some reproductive processes in the female golden hamster.

A single subcutaneous injection of 2 mg RMI 12,936 (17 beta-hydroxy-7 alpha-methylandrost-5-en-3-one) given a day after estrus disrupted estrous cycle for over 30 days and inhibited ovulation in 100 percent of treated Golden hamsters. Administration of RMI 12,936 (2 mg) on Day 6 of pregnancy caused termination of pregnancy within 4 days of treatment. In association with the termination of pregnancy was a significant reduction in the concentrations of progesterone and estradiol-17 beta together with an elevated testosterone level. After termination of pregnancy by RMI 12,936, the hamsters remained sexually receptive for 4 weeks but failed to conceive. It is concluded that RMI 12,936 causes termination of pregnancy due to an induction of functional luteolysis.

Abortion, Spontaneous

RMI 12,936 and pseudopregnancy in rats.

RMI 12,936, when injected subcutaneously at a dose of 2 mg, either on Day 6 of psuedopregnancy (PSP-6) or on PSP-6,7 and 8, shortened the duration of PSP from 12.3 +/- 0.3 (control) to 8.3 +/- 0.1 or 8.7 +/- 0.2 days, respectively. During PSP, plasma progesterone (delta 4P) levels in the peripheral plasma showed a trend of decrease by PSP-9 (52.0 +/- 4.6 on PSP-8 to 42.3 +/- 3.1 ng/ml on PSP-9). Administration of RMI 12,936 on PSP-6 resulted in a significant decrease in delta 4P and pregnenolone (delta 5P) within 24 hr after treatment but caused no apparent changes in 20 alpha-dihydroprogesterone (20 alpha-DHP) levels. However, a significant decrease of delta 4P/20 alpha DHP ratio was encountered 24 hr after RMI 12,936 treatment. The persistent occurrence of proestrous smear after PSP termination, but absence of estrous vaginal cytology, might be attributed to the slight estrogenicity of RMI 12,936. After the premature termination of pseudopregnancy induced by RMI 12,936, the female rats were sexually receptive for at least 3 weeks but failed to conceive, suggesting that this compound has a prolonged contraceptive effect.

Androstenols

Termination of pregnancy in the rat by RMI 12,936.

Administration of a steroid RMI 12,936 (2 MG) ON DAY 8 OF PREGNANCY RESULted in an interruption of gestation within 5 days. No significant changes in progesterone (delta 4P), 20 alpha-dihydroprogesterone (20 alpha-DHP) and pregnenolone (delta 5P) were recorded during the course of termination of pregnancy by RMI 12,936. However, a significant rise in serum delta 4P and hypertropic corpora lutea were evident on day 13 of pregnancy when all treated females showed dead conceptus. The placental tissue was still present at the time of pregnancy termination. On the other hand, serum LH levels was significantly suppressed 24 hr after the treatment and maintained at a very low level. The reduction of LH might be due to a lowered hypophyseal sensitivity towards LH-RH. The occurrence of in utero dead fetus without interference of delta 4P production suggests that in the rat RMI 12,936-induced termination of pregnancy is due to its embryotoxic rather than luteolytic effect. Although the treated females did not return to normal estrous cycles for a period of 2 weeks after pregnancy termination, they were sexually receptive. Successful mating resulted in normal pregnancy which occurred 30-35 days after RMI 12,936 treatment.

Abortifacient Agents

Termination of pseudopregnancy in rats by silastic-PVP-PGF2 alpha tube.

The efficacy of a one-end or both-end open Silastic-polyvinyl-pyrrolidone (Silastic-PVP) tube containing 600 microgram prostaglandin-F2 alpha (PGF2 alpha) and placed subcutaneously on day-6 of pseudopregnancy (PSP) in the induction of premature termination of PSP was compared. A both-end open Silastic-PVP-PGF2 alpha tube was more efficacious in inducing an early termination of PSP with a mean duration of 7.8 days. By contrast, PSP females receiving a one-end open Silastic-PVP-PGF2 alpha tube showed a mean duration of PSP of 9.9 days. The shortened duration of PSP in both these treatment groups was significantly different from the control value of 13.1 days. The significant drop in progesterone (delta 4P) but rise in 20 alpha-dihydroprogesterone (20 alpha-DHP) occurred 24 hr after treatment in PSP rats treated with both-end open Silastic-PVP-PGF2 alpha tube, whereas similar changes in delta 4P and 20 alpha-DHP took place 48-72 hr after the deposition of a one-end open Silastic-PVP PGF2 alpha tube. It is concluded than an initial larger amount of circulating PGF2 alpha is needed to induce an early premature termination of PSP. The exposure of corpus luteum to a more sustained but lower level of PGF2 alpha leads to a slower response.

20-alpha-Dihydroprogesterone

Inhibition of ovulation and fertilization by indomethacin and effect of prostaglandin-F2 alpha on early pregnancy in the rabbit.

Ovulation induced by HCG in rabbits was blocked by a single subcutaneous injection of 6 mg/kg indomethacin given 6 h after the insemination and HCG treatment. In addition, a time-dependent inhibition in the fertilization rate after indomethacin treatment was also recorded. This suggests that indomethacin, when given at a critical time and at an appropriate dose level, not only blocks ovulation but also interferes with fertilization. Treatment with graded amounts of prostaglandin-F2 alpha incorporated in a Silastic-polyvinylpyrrolidone-gel (PVP) had marginal to no effect after intravaginal placement on 4- or 6-day pregnancy. However, 5 mg PGF 2 alpha/ Silastic-PVP tube when placed intravaginally on Day-7 of pregnancy resulted in termination of pregnancy in 66% of the treated does. This implies that young corpora lutea are resistant of PGF2 alpha treatment and that pregnancy at the time of ovo-implantation can be terminated by PGF2 alpha incorporated in a Silastic-PVP tube.

Animals

Induction of mid-term abortion by trichosanthin in laboratory animals.

Trichosanthin, a protein purified from the extract of the root tuber of Trichosanthis Kirilowii, Maxim, given once only induced midterm abortion in the mice and rabbits. The effective I.P. dose for the induction of abortion in 10- or 11-day pregnant mouse was 50 micrograms. In the rabbit a dose and state of pregnancy-dependent response to Trichosanthin-induced abortion was encountered. A dose as low as 0.5 mg Trichosanthin in 22-day pregnant rabbit was adequate but 2.0 mg was needed in 17-day pregnant rabbit. Attempts to terminate pregnancy in the rat and hamster using Trichosanthin was not successful even with higher doses. When compared with prostaglandin-F2 alpha, an established abortifacient, Trichosanthin appeared to be more effective and associated with less side effects in the induction of abortion in the rabbit. Trichosanthin was ineffective to terminate early pregnancy in the 4 species studied.

Abortifacient Agents

Effects of 17 beta-hydroxy-7 alpha-methylandrost-5-en-3-one (RMI 12,936) on pregnant rabbits.

A single subcutaneous injection of RMI 12,936 interrupted 8- and 15-day pregnancy in the rabbit. A dose dependent loss of embryos was observed. Higher doses of RMI 12,936 were needed to terminate pregnancy in 8-day pregnant (74% efficacy with 10 mg/kg) than in 15-day pregnant rabbits (100% efficacy with 8 mg/kg). Termination of pregnancy by RMI 12,936 was accompanied by a significant increase of progesterone (delta 4 p) in rabbits receiving 10 mg/kg RMI 12,936 on day 8 of pregnancy. On the other hand, treatment with 8 mg/kg RMI 12,936 on day 15 of pregnancy did not alter the delta 4 p levels, but induced a significant decrease in 20 alpha-dihydroprogesterone. In these two treatment groups, a consistent and highly significant increase of serum testosterone (T) was observed. The increase of T value possibly was due to a decrease in aromatizing ability of the follicles after RMI 12, 936 treatment and might have contributed towards the interruption of pregnancy. The failure of RMI 12,936-treated rabbits to ovulate even after hCG administration suggests that his compound might have lowered the sensitivity of the mature follicles to LH stimulation.

Androstenols

Termination of pregnancy in rabbit and mouse by Trichosanthin.

The effects of a single intraperitoneal injection of Trichosanthin in 6-, 10-, 17- or 22-day pregnant rabbit (2 mg/rabbit) or in 11-day pregnant mouse (50 micrograms/mouse) were studied. Trichosanthin induced abortion in 100% of the 17- or 22-day pregnant rabbits within 48-72 hours and decreased circulating progesterone (delta 4P)concentrations with 24 hrs. On the other hand, the same dose failed to terminate pregnancy in 6- or 10-day pregnant rabbits and caused no significant changes in circulating delta 4P levels. Exogenous delta 4P or prolactin + human chorionic gonadotropin given twice daily failed to reverse the Trichosanthin-induced termination of pregnancy. However, this resulted in a delay of fetal expulsion. It is concluded that Trichosanthin-induced termination of pregnancy is not solely a result of luteolysis but is likely to be due to its toxic effects on placenta, embryo or both. A dose of 50 microgram Trichosanthin given to 11-day pregnant mice resulted in a termination of pregnancy within 96 hours and also a significant decrease in delta 4P levels in 24 hrs. The ratio of delta 4P to 20 alpha-dihydroprogesterone was also decreased steadily after Trichosanthin administration.

20-alpha-Dihydroprogesterone

Temporary sterility induced by intrascrotal deposition of silastic-polyvinylpyrrolidone-prostaglandin F2alpha tubes in the rabbit: effect on fetal survival after regain of fertility.

In male rabbits of proven fertility, the intrascrotal deposition of two Silastic-polyvinylpyrrolidone tubes containing 3 mg of prostaglandin F2alpha (PGF2alpha)/tube induced within 2 to 4 weeks temporary sterility which lasted for 10 to 14 weeks. Associated with induced sterility were reduction in testicular weight, increase in abnormal spermatozoa (8% to 78% versus 0 to 3.7%), and reduction in sperm motility along the reproductive tract and in the semen for a period of 6 to 7 weeks. During the period of temporary sterility the weight of the epididymis, the sexual drive, and semen volume remained unaltered. Normal fertility was associated with an increase in testicular weight, reduction in the proportion of abnormal sperm, and improved sperm motility. In addition to an altered spermatogenesis, the integrity of mature spermatozoa seemed to be severely affected after PGF2alpha treatment. The reduced number of viable young sired by males that recovered from temporary sterility (pregnancy wastage 35%) as compared with sham-treated controls (pregnancy wastage 3%) suggests that a small percentage of spermatozoa might still be defective at the time of testing. A longer waiting period might be needed to ensure a completely normal reproductive process.

Animals

Variations in serum androgens, estrogens, progestins, gonadotropins and prolactin levels in male rats from prepubertal to advanced age.

The concentrations of blood serum steroids from 12 to 450 days old male rats were determined by radioimmunoassay. Testosterone (T) was low (270 pg to less than 1 ng/ml) until day 42; adult levels (3--4 ng/ml) were attained by day 62 and declined tradually with advanced age. 5 alpha-dihydrotestosterone (5 alpha-DHT) did not change markedly (90--160 pg/ml) from prepubertal to advanced age. Except for a small peak on day 22, androstenedione (delta 4 A) levels ranged between 400-500 pg/ml in the adult but declined in older males. Progesterone (delta 4 P) rose steadily to a mean of 5.46 ng/ml at 52 days of age and dropped thereafter. High levels of estrone (268 +/- 38 pg/ml) and estradiol-17 beta (2.76 +/- 0.28 ng/ml) in 12 days old males are in contrast to the low estrogens (20-35 pg/ml) in adult animals. Both T/5 alpha-DHT and total T/estrogen ratios were low before puberty, increased in adults and decreased towards old age. The interplay between gonadotropin and prolactin, which exhibited reciprocal changes in the regulation of steroid production by the gonads with age, are discussed.

Aging

Age dependent changes in the sperm population and fertility in the male rat.

The entire reproductive tract was devoid of spermatozoa during the first 42 days of life. The first appearance of spermatozoa was detected in the caput epididymidis of 45-day old rats and in the cauda epididymidis of 52-day or older rats. The number of spermatozoa in the reproductive tract increased with age. The sperm population reached its maximum in the caput epididymidis by day-72 and in the caud epididymidis by day-100. These high levels were maintained beyond 450 days of age. Fifty-two day old male rats failed to impregnate the female. Although male rats of 62-500 days were able to sire litters, the peak reproductive period was found to be between days 100-270, during which the number of young per litter ranged between 11-16. Towards advanced age the litter size dropped to 8. The lower fertility in the males of advanced age might be due to a lower proportion of fertile spermatozoa, a change in the physiology of epididymis or an altered sperm transport in the reproductive tract.

Aging

Effects of cadmium chloride on testicular steroidogenesis and fertility of male rats.

Effects of a single subcutaneous injection of 1 or 5 mg/rat of cadmium chloride (CdCl2) on circulating steroids and fertility were studied over a period of 120 days in fertile male rats. Androgens and fertility returned to normal 120 days after 1 mg CdCl2 but males treated with 5 mg showed none to poor restoration of some of these parameters. The in vitro release of testosterone (T), 5 alpha-dihydrotestosterone (5 alpha-DHT) and androstenedione (delta 4A) by the decapsulated tests from CdCl2 treated males was significantly reduced whereas progesterone (delta 4P) was accumulated in significantly higher amounts into the incubation medium. When testes from CdCl2 treated males were incubated in vitro with hCG, a dose and time dependent stimulation of steroidogenesis was evident. Since the testes regained the steroidogenic capacity but the males remained sterile 120 days after 5 mg CdCl2 treatment, it appeared that CdCl2 induced a permanent damage to the germinal components of the testes.

Androgens

Effects of prostaglandin-F2alpha on some reproductive parameters of fertile male rats.

Silastic-PVP-PGF2alpha tubes significantly reduced the sperm population in the epididymis and vas-deferens of male rats 14 days after their insertion into the scrotal sacs. A reduction in testis and epididymal weights was also evident. The reduction of sperm population was accompanied by a normal sexual drive and circulating testosterone level and partial sterility. The reduction in sperm population and induction of partial sterility was detected at least 7 days after the total release of prostaglandin F2alpha from the Silastic-PVP tubes. The results suggest that the changes in the reproductive parameters might be a consequence of endocrinological and functional disturbances induced by PGF2alpha and that PGs can be used to induce temporary sterility in the male.

Animals

Prostaglandin F2alpha induced termination of pregnancy and its reversal by prolactin or progesterone in rats.

Intrauterine insertion of a Silastic-PVP tube containing 400 microgram PGF2alpha terminated midterm pregnancy in 100 per cent of the animals. Progesterone (2 mg/day) or prolactin (PRL) reversed the abortifacient effect of PGF2alpha. A dose- and duration-related effect of the PRL on PGF2alpha induced termination of pregnancy was evident. The results suggest that PGF2alpha and PRL are antagonistic to each other and multiple doses of PRL are needed to neutralize the luteolytic action of PGF2alpha.

Abortifacient Agents

Circulating plasma levels of pregnenolone, progesterone, estrogen, luteinizing hormone, and follicle stimulating hormone in young and aged C57BL/6 mice during various stages of pregnancy.

Young (3-5 mo of age) and senescent (12-15 mo of age) multiparous C57BL/6 mice were mated with young males (3-6 mo of age) and the numbers of preimplantation embryos and implantation sites determined on days 1 (day of plug), 4, 9, and 16 of pregnancy. The numbers of viable embryos were significantly lower (p less than 0.02 to p less than 0.001) in senescent females compared with young females on all days except day 1 of pregnancy. Plasma samples tested by radioimmunoassay indicated circulating estradiol-17B was significantly lower (P less than 0.05) on day 1 and higher (p less than 0.05) on day 4 in older females, whereas FSH was higher on days 4, 9, and 16 (p less than 0.02 to p less than 0.001) in senescent females when compared with samples from young females. Levels of pregnenolone, progesterone, estrone, and LH were not significantly different at any stage of pregnancy in the two age groups. From the hormonal data it did not appear that degenerating corpora lutea were responsible for the declining litter size in this strain of aged mouse.

Aging