Monoamine synthesis inhibitors have been used extensively to unravel the role of neurotransmitters in the hypothalamic regulation of pituitary LH release (Coppola, Leonardi & Lippmann, 1966; Kordon & Glowinski, 1972; Kalra, P.S. & McCann, 1973). Inhibition of tyrosine hydroxylase by α-methyl-paratyrosine (Corrodi & Hansen, 1966) or dopamine-β-hydroxylase by sodium diethyldithiocarbamate (Goldstein, Anagonste, Lauber & McKereghan, 1964) blocked the preovulatory discharge of LH and ovulation (Kalra & McCann, 1974). These pharmacological agents and a brain norepinephrine depletor, U-14,624 (1-phenyl-3-(2-thiazolyl)-2 thiourea (Johnson, Boukma & Kim, 1970), have been shown to suppress the release of pituitary LH induced by ovarian steroids (Kalra, Kalra, Krulich, Fawcett & McCann, 1972; Kalra, P.S. & McCann, 1973). These results were viewed as evidence for the involvement of a hypothalamic norepinephrine system in controlling LH release as suggested by Sawyer (1952). A single intraventricular injection of 6-hydroxydopamine to deplete norepinephrine and dopamine (Kostrzewa & Jacobowitz, 1974) reduced the LH-RH content of the hypothalamus (Kalra, 1975), but little other information is available to show that the depletion of brain catecholamines, and specifically norepinephrine, by these drugs results in modification of LH-RH secretion. In the present study the inhibition of pituitary LH release by the norepinephrine depletor, U-14,624, was investigated in ovariectomized rats.
M. R. N. PRASAD and S. P. KALRA
Clomiphene causes failure in implantation of blastocysts when administered to rats before implantation. This may be due either to a direct blastotoxic effect of the chemical or to elimination of blastocysts from the uterus. Further studies were made to elucidate the anti-implantation effect of the chemical. Clomiphene (0·3 mg/kg/day) was administered orally to rats on Day 9, Days 9 and 10, or Days 9, 10 and 11 after mating during experimentally induced delayed implantation. Uterine horns were flushed 24 hr after the last treatment. While 100% of the rats showed an average of four blastocysts/rat in initial controls, there was a marked reduction in the percentage (37·5) of rats showing blastocysts and in the number of blastocysts recovered from uteri of treated rats, depending on the dose and the time interval allowed for action of the compound. Ligation of uterine horns at the cervical end before treatment resulted in recovery of normal numbers of blastocysts in 75% of rats. These results indicate that blastocysts are expelled from non-ligated uteri. Initiation of oestrogen treatment (1μg/day) 6, 24 and 48 hr after first administration of clomiphene failed to cause implantation of blastocysts in ligated uteri. However, normal numbers of implantation sites were seen in the ligated horns of controls. It is, therefore, conceivable that failure of implantation following clomiphene administration may be due : (a) to increased motility of the uterus resulting in expulsion of the blastocysts; (b) to its anti-oestrogenic and/or antihistaminic activity which prevents preimplantation changes in the uterus normally initiated by exogenously administered oestrogen. Our results show that clomiphene has no direct cytolytic effects on the blastocysts.
S. P. KALRA and M. R. N. PRASAD
The effects of long-term administration of clomiphene on immature, intact male rats and their reproductive performance following cessation of treatment are reported. Clomiphene, at a dose of 250 μg/day or higher, inhibited spermatogenesis at the primary spermatocyte stage, the Leydig cells were atrophic and consequently the accessory glands were non-secretory. The testis resumed normal spermatogenesis immediately following withdrawal of treatment and spermatozoa appeared in the seminiferous tubules within 30 days of the period of recovery. The recovered males sired normal young when caged with virgin cycling females. It is suggested that the inhibitory effects on the testes and accessory glands following long-term administration of clomiphene are due to the oestrogenicity of the compound which may modify the synthesis and/or release of the gonadotrophins mediated through the hypothalamo-hypophysial axis.
The results are discussed in relation to the sequence of recovery of the gonads and accessory glands.
D. Caton, C. J. Wilcox and P. S. Kalra
Summary. Blood flow transducers were placed around one uterine artery per ewe and observations of the rate of blood flow through this artery and the peripheral plasma concentrations of free, unconjugated oestrone, oestradiol and progestagens were made at intervals of 1–3 days during the last 2–3 weeks of pregnancy and at hourly intervals after spontaneous delivery at term. Rates of uterine blood flow decreased on average by 50% or more within the first hours of parturition and patterns of change in blood flow varied considerably among the animals. Spontaneous daily (pre partum) and hourly (post partum) changes in uterine blood flow were significantly correlated (P < 0·01) with the product of the concentrations of progestagens and of total free oestrogens (oestrone and oestradiol) and with the product of progestagens and oestradiol in peripheral blood.
D. Caton, F. W. Bazer, P. S. Kalra and R. J. Moffatt
Summary. On Day 5 of pregnancy, before the blastocyst migrates to the uterus, one uterine horn was ligated to restrict the trophoblast to the lumen ipsilateral to the corpus luteum. The numbers of placentomes (caruncles and cotyledons) were reduced by half, but neither at 120 nor at 140 days of pregnancy (term 147 days) did the weights of placentae and fetuses of treated ewes differ significantly from those of control ewes. Amongst uterus-ligated animals prepared for chronic study, the rate of uterine blood flow (electromagnetic flow transducer, ml/min) to the pregnant horn was higher than in control ewes, as was the concentration of progestagens in maternal peripheral blood. There may be a compensatory response that causes hypertrophy of placentomes and that increases blood flow to the uterine horn containing placental tissue.
G. Singh, M. M. Singh, S. C. Maitra, W. Elger, V. Kalra, S. N. Upadhyay, S. R. Chowdhury and V. P. Kamboj
Summary. RU-38486 or ZK-98734 treatment (3 mg/day, s.c.) to intact or hysterectomized adult female rats on Days 5–7 post coitum induced changes characteristic of luteolysis. Ultrastructurally, the luteal cells exhibited an extensive vacuolization of the cytoplasm and perinuclear areas, degeneration of mitochondrial cristae, massive accumulation of lipid droplets, increase in number of lysosome like granules and heterochromatinization of the nucleus. In general, RU-38486 induced more marked degeneration of the luteal cells than did ZK-98734. There was also a significant decrease in peripheral plasma progesterone concentrations in treated rats. We suggest that these antiprogestagens act via inhibition of luteal function in addition to their antagonism at the uterine progesterone receptor level.
Keywords: antiprogestagens; ultrastructure; corpora lutea; progesterone; rat